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Cell-Membrane-Coated and Cell-Penetrating Peptide-Conjugated Trimagnetic Nanoparticles for Targeted Magnetic Hyperthermia of Prostate Cancer Cells
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Biological and Medical Applications of Materials and Interfaces

Cell-Membrane-Coated and Cell-Penetrating Peptide-Conjugated Trimagnetic Nanoparticles for Targeted Magnetic Hyperthermia of Prostate Cancer Cells
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  • Valentin Nica*
    Valentin Nica
    Istituto Italiano di Tecnologia, Smart Bio-Interfaces, Viale Rinaldo Piaggio 34, 56025 Pontedera, Italy
    *Email: [email protected]
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    Orcidhttps://orcid.org/0000-0002-5238-5657
  • Attilio Marino*
    Attilio Marino
    Istituto Italiano di Tecnologia, Smart Bio-Interfaces, Viale Rinaldo Piaggio 34, 56025 Pontedera, Italy
    *Email: [email protected]
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    Orcidhttps://orcid.org/0000-0002-3290-494X
  • Carlotta Pucci
    Carlotta Pucci
    Istituto Italiano di Tecnologia, Smart Bio-Interfaces, Viale Rinaldo Piaggio 34, 56025 Pontedera, Italy
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  • Özlem Şen
    Özlem Şen
    Istituto Italiano di Tecnologia, Smart Bio-Interfaces, Viale Rinaldo Piaggio 34, 56025 Pontedera, Italy
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  • Melis Emanet
    Melis Emanet
    Istituto Italiano di Tecnologia, Smart Bio-Interfaces, Viale Rinaldo Piaggio 34, 56025 Pontedera, Italy
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  • Daniele De Pasquale
    Daniele De Pasquale
    Istituto Italiano di Tecnologia, Smart Bio-Interfaces, Viale Rinaldo Piaggio 34, 56025 Pontedera, Italy
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  • Alessio Carmignani
    Alessio Carmignani
    Istituto Italiano di Tecnologia, Smart Bio-Interfaces, Viale Rinaldo Piaggio 34, 56025 Pontedera, Italy
    Sant’Anna School of Advanced Studies, The Biorobotics Institute, Viale Rinaldo Piaggio 34, 56025 Pontedera, Italy
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    Orcidhttps://orcid.org/0000-0002-6316-3478
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    Andrea Petretto
    IRCCS Istituto Giannina Gaslini, Core Facilities-Clinical Proteomics and Metabolomics, Via Gerolamo Gaslini 5, 16147 Genova, Italy
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  • Martina Bartolucci
    Martina Bartolucci
    IRCCS Istituto Giannina Gaslini, Core Facilities-Clinical Proteomics and Metabolomics, Via Gerolamo Gaslini 5, 16147 Genova, Italy
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  • Simone Lauciello
    Simone Lauciello
    Istituto Italiano di Tecnologia, Electron Microscopy Facility, Via Morego 30, 16163 Genova, Italy
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    Rosaria Brescia
    Istituto Italiano di Tecnologia, Electron Microscopy Facility, Via Morego 30, 16163 Genova, Italy
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    Francesco de Boni
    Istituto Italiano di Tecnologia, Materials Characterization Facility, Via Morego 30, 16163 Genova, Italy
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    Mirko Prato
    Istituto Italiano di Tecnologia, Materials Characterization Facility, Via Morego 30, 16163 Genova, Italy
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    Sergio Marras
    Istituto Italiano di Tecnologia, Materials Characterization Facility, Via Morego 30, 16163 Genova, Italy
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    Filippo Drago
    Istituto Italiano di Tecnologia, Electron Microscopy Facility, Via Morego 30, 16163 Genova, Italy
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  • Mohaned Hammad
    Mohaned Hammad
    University of Duisburg-Essen, Particle Science and Technology - Institute for Combustion and Gas Dynamics (IVG-PST), Carl-Benz Strasse 199, 47057 Duisburg, Germany
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  • Doris Segets
    Doris Segets
    University of Duisburg-Essen, Particle Science and Technology - Institute for Combustion and Gas Dynamics (IVG-PST), Carl-Benz Strasse 199, 47057 Duisburg, Germany
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    Orcidhttps://orcid.org/0000-0003-3102-2934
  • Gianni Ciofani*
    Gianni Ciofani
    Istituto Italiano di Tecnologia, Smart Bio-Interfaces, Viale Rinaldo Piaggio 34, 56025 Pontedera, Italy
    *Email: [email protected]
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    Orcidhttps://orcid.org/0000-0003-1192-3647
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ACS Applied Materials & Interfaces

Cite this: ACS Appl. Mater. Interfaces 2023, 15, 25, 30008–30028
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https://doi.org/10.1021/acsami.3c07248
Published June 13, 2023

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Abstract

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Prostate malignancy represents the second leading cause of cancer-specific death among the male population worldwide. Herein, enhanced intracellular magnetic fluid hyperthermia is applied in vitro to treat prostate cancer (PCa) cells with minimum invasiveness and toxicity and highly specific targeting. We designed and optimized novel shape-anisotropic magnetic core–shell–shell nanoparticles (i.e., trimagnetic nanoparticles - TMNPs) with significant magnetothermal conversion following an exchange coupling effect to an external alternating magnetic field (AMF). The functional properties of the best candidate in terms of heating efficiency (i.e., Fe3O4@Mn0.5Zn0.5Fe2O4@CoFe2O4) were exploited following surface decoration with PCa cell membranes (CM) and/or LN1 cell-penetrating peptide (CPP). We demonstrated that the combination of biomimetic dual CM-CPP targeting and AMF responsiveness significantly induces caspase 9-mediated apoptosis of PCa cells. Furthermore, a downregulation of the cell cycle progression markers and a decrease of the migration rate in surviving cells were observed in response to the TMNP-assisted magnetic hyperthermia, suggesting a reduction in cancer cell aggressiveness.

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1. Introduction

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Magnetic-fluid-mediated hyperthermia (MFH) is a promising technique for cancer treatment, proved by successful human clinical trials, (1) and it is exploited in many types of tumors such as brain, (2) prostate, (3) breast, (4) and pancreatic (5) cancer. Prostate cancer (PCa) remains a very important key health concern, and it is the most common cancer in males worldwide. For instance, the malignant neoplasm of the prostate is a leading cause of death in men in Europe, accounting for 65 200 cases (2.9% of all male deaths) in 2018. (6)
Recent attainments of MFH in PCa are very promising; however, the method needs further development for clinical implementation, and (7) the selection of the most suitable material and procedure aiming at efficient MFH is still a persistent matter of debate. (8) Nevertheless, the development of high-efficiency nanoheaters showing a high specific absorption rate (SAR) value is a requisite for clinical application to overcome several limitations related to the nanoparticle quantity used in therapy and thus to their consequent toxicity. (9) The toxicity of magnetic nanoparticles (MNPs) can indeed depend on many factors, such as size, shape, surface coating, composition, concentration, exposure time, route of administration, pharmacokinetics, and biodegradability. (10−12) Some of the possible mechanisms of toxicity include oxidative stress, inflammation, genotoxicity, and immunotoxicity. (13,14) These effects can vary depending on the type of cells or tissues that interact with the MNPs and their biological environment. (13) Therefore, it is important to optimize the design of MNPs to minimize their toxicity and maximize their therapeutic effectiveness. Some of the strategies to achieve these purposes include choosing appropriate biocompatible materials and coatings, controlling the size and shape distribution, enhancing the stability and solubility, reducing the aggregation and sedimentation, regulating the mechanisms of local induction of heat in subcellular compartments, and improving the targeting and responsiveness of MNPs. (15,14)
There is rich scientific literature that outlines the improvement of SAR values by optimizing various chemical–physical parameters of the nanoparticles such as shape anisotropy, magnetic shell thickness, magnetic anisotropy, size, and cation distribution inside nanocrystals, or stability in polar and nonpolar solvents. (16,17) It has been demonstrated that bimagnetic nanoparticles (BMNPs) have a SAR value of one order magnitude higher than single core nanoparticles. (18) Other studies focused on magnetic systems in the ferromagnetic regime, (19) whereas MNPs with superparamagnetic characteristics are more desirable for inductive hyperthermia. In addition, shape-anisotropic MNPs play a key role in increasing SAR for heat-mediated hyperthermia. (20) We reported that superparamagnetic truncated-octahedron (ZnxCo1–xFe2O4@MnFe2O4) (21) and spherical (Zn0.4Co0.6Fe2O4@ Zn0.4Mn0.6Fe2O4) (22) BMNPs are highly efficient in hyperthermia therapy. In another study, we synthesized polyhedron-shaped BMNPs (Zn0.4Co0.6Fe2O4@Zn0.4Mn0.6Fe2O4) which exhibit superparamagnetic properties and a 2-fold increase of SAR with respect to the core nanoparticles with the same volume and composition. (23) However, there is a need to find new effective ways to demonstrate the therapeutic local effect of magnetic heat dissipation into the cell structure. For instance, intracellular hyperthermia has been claimed as an efficient strategy to increase apoptosis in glioblastoma cells. (24)
There are few papers reporting on the synthesis and characterization of trimagnetic nanoparticles (TMNPs). Isaac et al. reported on spherical multishell MnFe2O4@CoFe2O4@NiFe2O4 nanoparticles; (25) these nanoparticles, having a mean size of 11 nm, behave as ferromagnetic structures with a mild saturation magnetization (MS = 65 emu/g). Other researchers reported the fabrication of onion-like Fe3O4/MgO/CoFe2O4 core–shell–shell nanostructures with the magnetite mean core size of 22 ± 4 nm coated with an inner shell of magnesium oxide and an outer core of cobalt ferrite of thicknesses ≈1 and ≈2.5 nm, respectively. The magnetization measurements at the temperature T = 5 K revealed enhancement of the coercivity field, from HC ≈ 48.3 kA/m for the Fe3O4/MgO to HC ≈ 468.7 Oe for the Fe3O4/MgO/CoFe2O4 nanoparticles, attributed to the magnetic coupling between both ferrimagnetic phases. (26) To the best of our knowledge, no investigations about SAR assessment of this kind of nanoparticles can be found in the literature, thus representing TMNPs as a viable alternative to conventional hyperthermia where high doses of therapeutic agents are required. (27−29)
Current research shows that the therapeutic efficacy of MFH is limited by poor stabilization of MNPs in aqueous environments and their bioavailability or by the lack of targeting specificity in tumors. (30) By overcoming these limitations, the functionalization of MNPs with a biomimetic coating may significantly improve the feasibility of PCa therapy. (31,32) Cell membranes exhibit unique functional components that can improve biocompatibility, cellular uptake, tumor-specific targeting, and site accumulation. (33) Some authors reported an enhancement of both magnetic resonance imaging (MRI) signal and MCF-7 human breast tumor photothermal therapy efficiency following the functionalization of Fe3O4 nanoparticles with red blood cell membrane-derived vesicles. (34) In another example, a myeloid-derived suppressor cell membrane was coated onto spherical Fe3O4 nanoparticles to target C–C or C–X–C chemokine receptors. (35) Cell-penetrating peptides (CPPs) are instead known to facilitate targeting with limited toxicity (27) and noninvasiveness: (36) very recently, a novel tissue-specific CPP displayed high targeting affinity for LNCaP prostate cancer cells in vivo. (37) LN1 showed cell-specific selectivity to tumor tissue, avoiding adverse reactions on healthy liver and kidney cells.
In the current study, we designed and developed novel magnetically core–shell–shell nanoparticles (namely trimagnetic nanoparticles, TMNPs) with enhanced SAR for intracellular hyperthermia against PCa cells. We demonstrated that the functionalization of lipid-PEGylated TMNPs with both cell membrane (CM) and LN1 CPP induces a strong selectivity for PCa cells. We therefore investigated the therapeutic effects of TMNPs-mediated hyperthermia, evaluating cellular death, migration rate, and molecular mechanisms at the base of the observed phenomena.

2. Experimental Section

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2.1. Synthesis of Bimagnetic (BMNPs) and Trimagnetic Nanoparticles (TMNPs)

Trimagnetic nanoparticles (TMNPs) with magnetic core–shell–shell architecture have been synthesized in a two-step procedure by thermal decomposition of metallic complexes and a subsequent one-step seed-mediated growth route. In the first step, highly monodispersed core–shell bimagnetic nanoparticles (BMNPs) have been obtained in a slightly modified one-pot synthesis. (38) For a magnetically soft–soft system (Fe3O4@Mn0.5Zn0.5Fe2O4, further noted as SS), 1.334 mmol of iron(III) acetylacetonate (Fe(acac)3, 99%, Aldrich), 0.333 mmol of manganese(II) acetylacetonate (Mn(acac)2, 95%, Aldrich), and 0.333 mmol of zinc acetylacetonate (Zn(acac)2, 98%, Aldrich), were added in a solution of 6 mmol of 1,2-hexadecandiol (98%, Sigma-Aldrich), 6 mmol of oleic acid (90%, Aldrich), and 6 mmol of oleylamine (98%, Sigma-Aldrich) in 20 mL of benzyl ether (98%, Sigma-Aldrich). The mixture was mechanically stirred under nitrogen flow and heated at 80 °C for 240 min under vacuum. Then the reaction mixture was heated at 200 °C for 2 h and to reflux for 1 h with a heating rate of 12 °C/min. The particles were washed three times with ethanol (99%, Sigma-Aldrich) and hexane (99.9%, Carlo Erba) and separated by centrifugation (10 min, 10000g, 4 °C, Thermo Scientific Sorvall Lynx 4000). In the second step, 80 mg of BMNPs dispersed in chloroform (99.8%, Sigma-Aldrich) was added to a reaction system containing 0.250 mmol of Fe(acac)3, 0.125 mmol of cobalt(II) acetylacetonate (Co(acac)2, 99.9%, Aldrich), 3 mmol of oleic acid (OA), and 3 mmol of oleylamine (OAm). To grow the second magnetic shell (i.e., CoFe2O4) on the surface of the BMNPs, we used similar experimental conditions described in the first step but with a reaction time of 30 min under reflux. After three cleaning and centrifugation steps, the Fe3O4@Mn0.5Zn0.5Fe2O4@CoFe2O4 magnetic soft–soft–hard TMNPs (SSH) were dispersed in chloroform.
Analogously, by changing the molar ratio of metallic compounds for each sample and its core–shell–shell architecture, we synthesized another type of BMNPs (Fe3O4@Co0.5Zn0.5Fe2O4, indicated as SH) and of TMNPs with magnetic soft–hard–soft architecture (Fe3O4@Co0.5Zn0.5Fe2O4@MnFe2O4, indicated as SHS), respectively. The experimental conditions (i.e., synthesis time, reflux time, nitrogen flux, cleaning steps) for these samples were similar to those described for SS and SSH, respectively.

2.2. Water-Phase Transfer of SH, SHS, SS, and SSH MNPs

The thermal decomposition procedure provides magnetic nanoparticles dispersed in organic solvents unsuitable for most biological purposes. In a typical synthesis route, the hydrophobic SSH MNPs were thus transferred to an aqueous medium by exploiting a dual solvent exchange protocol. (39) The method provides high water dispersibility through phospholipid–PEG coating, with desirable reactive groups on the MNP surface. To facilitate the ligand exchange, 3.2 mL of SSH MNPs dispersed in chloroform (16 mg Fe/mL) was added to a mixture containing a 3:1 weight ratio of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-5000] (ammonium salt) (DSPE-mPEG, 5000 Da, Nanocs, Inc.)/1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[maleimide(polyethylene glycol)-5000] (ammonium salt) (DSPE-PEG maleimide, 5000 Da, Avanti Polar Lipids). The amount of phospholipid–polymer dissolved in chloroform was calculated as a 1:2 weight ratio between polymers and iron content. An amount of 60 mL of dimethyl sulfoxide (DMSO, 99.9%, Thermo Scientific) was dripped gradually during the reaction, and the resulting mixture was incubated on a shaker at 25 °C for 1 h. The chloroform was removed overnight under vacuum; afterward, 30 mL of Milli-Q water (Millipore) was added to form a colloidal dispersion. The excess amphiphilic micelles and DMSO have been removed by three centrifugation steps (20 min, 10000g, 10 °C). The coated SSH MNPs were finally redispersed in 4 mL of Milli-Q water and denoted as L-SSH.
Using a similar coating procedure, SHS, SS, and SH MNPs have been transferred into an aqueous medium and further denoted as L-SHS, L-SS, and L-SH MNPs, respectively.

2.3. Functionalization of L-SSH MNPs with a Cell Membrane and Cell-Penetrating Peptide

L-SSH MNPs have been functionalized with CM or with LN1 CPP similarly as previously reported by our group. (40,41) A double functionalization with CM/LN1 has been considered as well.

2.3.1. Cell Membrane Extraction

PCa-derived cell membranes have been obtained via hypotonic cell lysis, mechanical membrane disruption by high-pressure homogenization, and differential centrifugation. The PC-3 (ATCC CRL-1435) caucasian prostate adenocarcinoma cell line has been used for cell membrane extraction. PC-3 cells were cultured using the Gibco Roswell Park Memorial Institute 1640 medium (RPMI, Gibco, ThermoFisher) supplemented with 1% penicillin–streptomycin (P/S), 1% l-glutamine, and 10% fetal bovine serum (FBS, Sigma-Aldrich). PC-3 cells (104 cells/cm2) were seeded in 10 cm diameter Petri dishes treated for cell culture (Corning). When the cells grew at about 90% of confluence, they were washed twice with Dulbecco’s phosphate buffer saline solution (DPBS, Euroclone) and detached in 4 mL of DPBS per dish. After a centrifugation step (660g for 5 min), pellets were resuspended in cold (4 °C) Milli-Q water, and cells were disrupted with a high-pressure homogenizer (20 psi). Samples were centrifuged at 10000g for 10 min at 4 °C, and the supernatant containing CM was collected and further centrifuged at 37000g for 60 min at 4 °C. The obtained pellet was finally resuspended in 1 mL of Milli-Q water.

2.3.2. L-SSH MNP Coating with a Cell Membrane

An amount of 1 mL of CM extract derived from 5 × 106 cells was used to coat 2 mg of L-SSH MNPs dispersed in Milli-Q water (2 mg/mL). The membrane coating was attained through ultrasonic high power (25 W) treatment (20 kHz, Fisherbrand Q125 Sonicator, FisherScientific) with intermittent pulse timing mode (2 s pulse, 30 min) in an ice bath. The sample was thereafter washed three times with deionized water and susequently collected by centrifugation (16000g, 90 min, 4 °C). The pellet was eventually disersed in 1 mL of Milli-Q water and the final product indicated as CM-L-SSH.

2.3.3. Functionalization of L-SSH MNPs with an LN1 Cell-Penetrating Peptide

The L-SSH MNP surface was modified with a CPP (LN1, 95%, CTGTPARQC sequence, ProteoGenixSAS) using maleimide–thiol Michael addition click reaction involving the DSPE-PEG maleimide terminal group and the cysteine end group of the peptide sequence. An amount of 50 μL of LN1 peptide aqueous solution (1 mg/mL) was mixed with 1 mL of L-SSH dispersion (4 mg/mL) and diluted with PBS to a neutral pH for site-selective reaction of cysteine. The product was maintained in an ice bath and gently shaken for 4 h in the dark. Then, the sample was washed through centrifugation (16000g, 90 min, 4 °C) three times and eventually dispersed in 1 mL of Milli-Q water. The sample is named LN1-L-SSH.

2.3.4. Functionalization of L-SSH MNPs with a Cell Membrane and LN1 Cell-Penetrating Peptide

An amount of 1 mL of CM and LN1 (10:1 w/w) aqueous solution (pH ∼ 7) was added into 1 mL of L-SSH MNP dispersion (4 mg/mL) under high power intermittent sonication (25 W, 2 s/pulse, 30 min) at 4 °C. Then, the mixture was placed in an ice bath on a shaking plate for 4 h in the dark. The sample followed the same procedure of cleaning and centrifugation as previously described, and finally, it was dispersed in 1 mL of Milli-Q water. The sample is named CM-LN1-L-SSH. A representative illustration of CM-LN1-L-SSH MNP preparation and their application for in vitro prostate cancer treatment is presented in Figure S1 (Supporting Information), while the schematic representation of MNPs’ coating and their functionalization is given in Figure 1.

Figure 1

Figure 1. Schematic illustration of coating and functionalization procedures of BMNPs and TMNPs: Fe3O4@Co0.5Zn0.5Fe2O4, soft–hard (SH); Fe3O4@Co0.5Zn0.5Fe2O4@MnFe2O4, soft–hard–soft (SHS); Fe3O4@Mn0.5Zn0.5Fe2O4, soft–soft (SS); (c) Fe3O4@Mn0.5Zn0.5Fe2O4@CoFe2O4, soft–soft–hard (SSH).

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2.3.5. Fluorescence Staining

For confocal microscopy imaging, L-SSH, CM-L-SSH, LN1-L-SSH, and CM-LN1-L-SSH MNPs were stained with a fluorescent lipophilic dye (Vybrant DiO, ThermoFisher) by incubating 1 mg of nanoparticles with 10 μL of dye (2 h, 37 °C). The samples were washed three times by centrifugation (16 000g, 90 min, 4 °C) before use.

2.4. Physical–Chemical Characterization

Bright-field (BF) transmission electron microscopy (TEM) micrographs were obtained with a JEOL JEM-1011 (JEOL Ltd.) operated at 100 kV. The samples were gently sonicated (5 min), and a drop of the suspension was dried on a carbon-coated Cu grid (150 mesh). The mean diameter of pristine MNPs has been obtained by Gaussian fitting of the size distribution curve using the ImageJ software package (42) (version 1.53s). For CM-L-SSH and CM-LN1-L-SSH MNPs, the samples were gently sonicated (5 min), and a drop of the suspension was dried on a carbon-coated Cu grid (150 mesh). To highlight the lipid coating, the samples were negatively stained with a solution of 1% uranyl acetate in water for 30 s, and then TEM grids were dried in air. Energy-filtered TEM (EFTEM) imaging was carried out on an image-Cs-corrected JEOL JEM-2200FS transmission electron microscope (TEM) equipped with an in-column imaging filter (Ω-type), operated at 200 kV. The EFTEM elemental mapping was obtained by the three-window method at the L23 edges of Mn (onset E = 640 eV, slit width ΔE = 30 eV), Co (E = 779 eV, ΔE = 16 eV), Fe (E = 708 eV, ΔE = 16 eV), and Zn (E = 1020 eV, ΔE = 60 eV): width and position of the energy-selecting slit were optimized to minimize overlaps from neighboring ionization edges.
Scanning electron microscopy (SEM) has been used to assess the morphology of the samples and, in particular, the shape of the nanoparticles. Images were acquired by using a Helios NanoLab 600 DualBeam FIB/SEM (FEI) instrument (voltage of 2 kV, beam current of 0.04 nA, and dwell time set to 8 μs). The samples were prepared by dropping the nanoparticle dispersion directly on a carbon-coated holder and drying at room temperature under a flow of argon gas.
X-ray photoelectron spectroscopy (XPS) measurements were carried out through a Kratos Axis UltraDLD spectrometer (Kratos Analytical Ltd.) with a monochromated Al Kα X-ray source (hν = 1486.6 eV) operating at 20 mA and 15 kV. The specimens were prepared by pressing a low amount of fine-grounded sample onto a high-purity indium pellet (99.9%, Sigma-Aldrich). The wide scans were collected over an analysis area of 300 × 700 μm2 at a photoelectron pass energy of 160 eV and energy step of 1 eV, while high-resolution spectra were collected at a photoelectron pass energy of 20 eV and an energy step of 0.1 eV. Differential electrical charging effects on the surface of the sample were neutralized during the measurements of all specimens. The spectra have been referenced to the adventitious carbon 1s peak at 284.8 eV. The spectra were analyzed with the CasaXPS software (Casa Software Ltd., version 2.3.24), (43) and the residual background was eliminated by the Shirley method.
Inductively coupled plasma optical emission spectroscopy (ICP-OES, iCAP-7600 DUO, ThermoFisher) has been performed to evaluate the elemental composition of pristine BMNPs and TMNPs (SH, SS, SHS, and SSH MNPs). The samples were digested with 800 μL of nitric acid (HNO3 60% v/v) and 200 μL of hydrogen peroxide (H2O2 30%) under sonication (65 °C for 2 h). Before measurements, 100 μL of each sample was diluted in a 10 mL vial by adding deionized water. All measurements have been carried out using a plasma power of 1150 W, a nebulizer gas flow of 0.5 L/min, a cooling flow of 12 L/min, and an auxiliary flow of 0.5 L/min. The amount of Co, Mn, Zn, and Fe was determined. All chemical analyses performed by ICP-OES were affected by a systematic error of 5%.
X-ray diffraction (XRD) analysis was performed on a third-generation Empyrean X-ray diffractometer (Malvern Panalytical), equipped with a MoKα (λ = 0.71 Å) ceramic X-ray tube (60 kV, 40 mA) and a GaliPIX3D solid-state pixel detector. The diffraction patterns were collected in environmental atmosphere at room temperature within the range 2θ = 20–100°. The samples gripped on mylar foil substrate were mounted in a reflection-transmission spinner sample stage (rotation speed = 1 rps) and analyzed in transmission geometry. The mean crystallite size (dXRD) and the lattice constant (a) were calculated from the diffractograms through the Pawley method (PANalytical Software version 3.0, PANalytical B.V.), (44) which uses whole-pattern profile fitting of the XRD pattern without a structural model.
The size distribution and Z-potential analyses of L-SSH, CM-L-SSH, LN1-L-SSH, and CM-LN1-L-SSH MNPs were performed by using a Zetasizer Nano ZS90 (Malvern Instruments, Ltd.). The measurements have been performed on 100 μg/mL nanoparticle dispersions in Milli-Q water at 37 °C with a scattering angle of 90°. The mean hydrodynamic diameter and polydispersity index (PDI) parameters were determined from the fitting (cumulant analysis) of the measured intensity by autocorrelation function. The Z-potential was determined by adjusting the conductivity of the sample in the range 10–100 μS/cm. The stability of L-SSH and CM-LN1-L-SSH MNPs, respectively, in Milli-Q water, DMEM, and PBS was assessed by evaluating the trend of the hydrodynamic diameter over time (up to 1 month). Under the same experimental conditions, the stability study of CM-LN1-L-SSH MNPs has been performed in a serum-containing physiological simulated medium, i.e., 90% DMEM + 10% FBS. Each measurement has been performed in triplicate, on three different sample preparations.
Thermogravimetric analysis (TGA) was carried out by using a TGA Q50 device (TA Instruments). L-SSH, CM-L-SSH, LN1-L-SSH, and CM-LN1-L-SSH nanoparticles were analyzed within the temperature range of 30–600 °C under a N2 flow (50 mL/min).
The bicinchoninic acid assay (BCA) quantification method is generally used in the literature to quantify peptide/protein functionalization in inorganic and hybrid membrane-derived nanoparticles with high sensitivity. (45,46) It has been thus exploited (Pierce Protein Assay Kit, Thermo Scientific) to quantify the protein amount on CM-, LN1-, and CM/LN1-functionalized L-SSH MNPs. A standard protocol provided by the manufacturer was followed. Briefly, 25 μL of 4 mg/mL dispersion of each kind of nanoparticle (CM-L-SSH, LN1-L-SSH, CM-LN1-L-SSH MNPs) was mixed with 200 μL of standard assay solution on the microplate. The specimens were incubated at 37 °C on a shaker (60 rpm) for 30 min and subsequently centrifuged (10 min at 14000g). The supernatant of each sample was collected, and its absorbance (λ = 560 nm) was assessed with a UV–vis plate reader (Victor X3, PerkinElmer). For the LN1 quantification, the absorbance of L-SSH MNPs was subtracted. The protein amount was calculated using a calibration curve (0–1000 μg/mL albumin standard) and expressed for 1 mg/mL of solution.
The magnetic characterization has been carried out using a Physical Property Measurement System (Quantum Design PPMS DynaCool, Quantum Design). All experiments were performed at room temperature (300 K) over a maximum applied magnetic field of B = ±9 T.
Magnetic inductive measurements were performed using a MagneTherm instrument (NanoTherics) running at an applied external alternating magnetic field (AMF) of B = 20 mT (H = 15.9 kA/m) and a frequency f = 97.5 kHz. The specific absorption rate (SAR) was determined for the quantification of the heat dissipation rate of L-SHS, L-SH, L-SSH, and L-SS MNPs dispersed in an aqueous medium. A vial containing 100 μL of MNP ferrofluid sample with a concentration of 5 mg/mL was wrapped in styrofoam to reduce heat losses and placed at the center of a 17-turn water-cooled magnetic induction coil. The specimens were thermostated at an initial temperature of T0 = 298.15 K and then exposed to the AMF for 7 min. The temperature change over time was recorded using a fiber optic temperature sensor (OSENSA Innovations Corp.). The heating efficiency has been calculated using the corrected-slope method in agreement with eq 1: (47)
SAR=(CdTdt+LΔT)/m
(1)
where C is the specific heat capacity of water (4.182 J/kg K), dT/dt is the initial slope of the time vs temperature curve, L represents the linear loss parameter, ΔT is the average temperature difference between the sample and baseline, and m represents the mass of the nanoparticles.
At a low-frequency regime and low field strength, the intrinsic loss parameter (ILP) has been considered (36) to compare the heating efficiency in various experimental conditions independently from the applied AMF characteristics (eq 2):
ILP=SARfH2
(2)
where H represents the intensity of the applied field and f is the excitation frequency.

2.5. Biological Characterization

2.5.1. Cell Viability Assays

The cytotoxicity tests were performed on the PC-3 (ATCC CRL-1435) Caucasian prostate adenocarcinoma cell line and on human primary normal prostate epithelial cells (ATCC-PCS-440-010). PC-3 cells were cultured in T175 flasks using the RPMI 1640 medium (Sigma) supplemented with 10% fetal bovine serum (FBS), 100 IU/mL of penicillin (Gibco), 100 μg/mL of streptomycin (Gibco), and 2 mM l-glutamine (Gibco). Human primary normal prostate epithelial cells were cultured with Prostate Epithelial Cell Basal Medium (ATCC) supplemented with Prostate Epithelial Cell Growth Kit (ATCC) as described by the manufacturer protocol. Cell viability was assessed using the WST-1 assay (Roche). PC-3 and human primary normal prostate epithelial cells were seeded in 24-well plates at the density of 15 × 103 cells/cm2, and cell viability was evaluated upon 72 h treatment with L-SSH MNPs at increasing concentrations (0, 30, 85, 250, 500, and 700 μg/mL). Cultures were incubated with 300 μL of phenol red-free complete medium with the WST-1 reagent (1:20 dilution) for 30 min at 37 °C; thereafter, the absorbance of the supernatant was measured at 450 nm using a Victor X3 (PerkinElmer) UV–Vis plate reader. The absorbance values were expressed as % with respect to the control.

2.5.2. Targeting Efficiency of L-SSH, CM-L-SSH, LN1-L-SSH, and CM-LN1-L-SSH MNPs

The cellular uptake was assessed by confocal laser scanning microscopy (CLSM) imaging (C 2s, Nikon). In a typical route, the PC-3 cells were seeded on WillCo glass dishes (15 × 103 cells/cm2), incubated at 37 °C, and treated for 72 h with 250 μg/mL of dye-labeled L-SSH MNPs. Then, the sample was washed twice with PBS, fixed with 4% paraformaldehyde (PFA, Sigma-Aldrich) for 30 min at 4 °C, and finally stained with tetramethylrhodamine (TRITC)-phalloidin (100 μM, Millipore) and Hoechst 33342 (1 μg/mL, Invitrogen). The same procedure was performed for CM-L-SSH, LN1-L-SSH, and CM-LN1-L-SSH MNPs. Due to the superior targeting ability of CM-LN1-L-SSH MNPs to target PC-3 cells, the following experiments on magnetothermal stimulation have been carried out using this sample.
ICP-OES has been performed to evaluate the intracellular uptake of functionalized MNPs (L-SSH, CM-L-SSH, LN1-L-SSH, and CM-LN1-L-SSH MNPs). For the quantitative analysis of functionalized MNP internalization, PC-3 cells were seeded in T75 flasks (15 × 103 cells/cm2) for 72 h, washed twice with PBS, detached with 0.05% trypsin-EDTA, and centrifuged. Then, the samples were digested and measured in a similar manner used for the ICP-OES analysis of pristine MNPs (SH, SHS, SS, and SSH MNPs). Finally, data were normalized for the nonfunctionalized controls (L-SSH MNPs).

2.5.3. Magnetothermal Stimulation

The effects of CM-LN1-L-SSH MNP-mediated hyperthermia on cell viability, proliferation, apoptosis, and necrosis have been investigated under magnetothermal stimulation. PC-3 cells were seeded (15 × 103 cells/cm2) and treated with 250 μg/mL of CM-LN1-L-SSH MNPs in HEPES-supplemented complete medium to keep the pH value stable during the AMF stimulation. Nonstimulated cultures were kept outside of the incubator for 100 min in HEPES-supplemented complete medium. Similarly as previously performed, (18,41) the cultures underwent alternating magnetic field (AMF) stimulations (f = 97.5 kHz, B = 20 mT; 100 min/day stimulation over 3 days) after 24 h of magnetic nanoparticle incubation. CM-LN1-L-SSH MNP-treated AMF-stimulated cells (“CM-LN1-L-SSH MNPs + AMF”) were compared to nontreated nonstimulated control cells (“L-SSH MNPs”) as well as to samples stimulated with AMF but not treated with nanoparticles (“L-SSH MNPs + AMF”) and cells incubated with 250 μg/mL of CM-LN1-L-SSH MNPs but not stimulated with AMF (“CM-LN1-L-SSH MNPs”). WST-1 cell viability assay for the evaluation of CM-LN1-L-SSH MNP effects after the hyperthermia treatment has been carried out as described above.
The intraparticle temperature was recorded by CLSM using the DiI fluorescent dye similarly as previously described. (48) Briefly, 0.5 mL of CM-LN1-L-SSH MNP (6 mg/mL) were stained with 20 μL of DiI staining solution (Vybrant Multicolor Cell-Labeling Kit, Invitrogen, ThermoFisher) for 30 min. Subsequently, the nanoparticles were washed 3 times by centrifugation and discarding the supernatant. PC-3 cells were seeded at 15 × 103 cells/cm2 density and then treated with 250 μg/mL of DiI-stained CM-LN1-L-SSH MNPs. At 24 h of incubation, the cultures underwent alternating magnetic field (AMF) stimulations (by using the live cell coil of the MagneTherm equipment, NanoTherics; f = 97.5 kHz, B = 20 mT). During stimulation, time-lapse CLSM imaging was carried out with a confocal fluorescence microscope (CS2, Nikon) using the perfect focus configuration. To avoid objective heating during AMF, the microscope revolver was lowered by using the escape modality at the end of each acquisition (NIS-Elements software). The objective was automatically positioned in the perfect focus position just before carrying out the image acquisition. The fluorescence intensities of the regions of interest were then converted to temperatures by using the ΔF/F0 = −0.0224·ΔT linear function. (41)

2.5.4. Immunofluorescence

Immunofluorescence was performed on “Control”, “Control + AMF”, “CM-LN1-L-SSH MNPs”, and “CM-LN1-L-SSH MNPs + AMF” experimental classes.
For the analysis of the Ki-67 proliferation marker, the following procedure has been performed: after AMF stimulation, the cultures were washed three times with PBS, fixed with 4% PFA for 30 min at 4 °C, and then processed for immunofluorescence. Specifically, cell membranes were permeabilized by using Triton X-100 solution (0.1% v/v dilution, Sigma-Aldrich) in PBS for 30 min at room temperature. A blocking step was carried out by incubating samples with 10% goat serum in PBS for 45 min at room temperature. A 90 min treatment with a primary rabbit IgG anti-Ki-67 antibody (1:150 dilution in PBS, Millipore) was performed at 37 °C. After subsequent washing steps (four times, 5 min each, by using PBS supplemented with 10% goat serum), cells were incubated with a 10% goat serum solution in PBS supplemented with a goat Alexa Fluor 488-IgG antirabbit secondary antibody (1:150 dilution, Invitrogen), Hoechst 33342 (1 μg/mL) for nuclei staining, and TRITC-phalloidin (120 μM) for F-acting staining. CLSM was carried out with a C 2s system (Nikon) using the autofocus mode and the same acquisition parameters for all samples. The total number of cell nuclei and of Ki-67+ nuclei were counted in semiautomatic mode with the NIS-Elements software (Nikon) using the same signal thresholding parameters for the different experimental classes.
The heat shock protein 70 (hsp70) is a chaperone protein overexpressed in cancer cells exposed to magnetic fluid hyperthermia. (70) For the analysis of hsp70 expression, the same procedures described above for Ki-67 immunofluorescence have been followed, but an anti-hsp70 rabbit polyclonal IgG primary antibody (1:200 dilution, Genetex) and an Atto 488 goat antirabbit secondary antibody (1:300 dilution, Sigma-Aldrich) have been used. CLSM was carried out with a C 2s system (Nikon) using the autofocus mode and the same acquisition parameters. Finally, the signal intensity of hsp70 was measured using the NIS-Elements software (Nikon).

2.5.5. Flow Cytometry

Flow cytometry analysis was carried out on “Control”, “Control + AMF”, “CM-LN1-L-SSH MNPs”, and “CM-LN1-L-SSH MNPs + AMF” experimental classes.
For the analysis of apoptosis and necrosis, cells after magnetothermal treatment were washed twice with PBS without Ca2+ and Mg2+ and detached with 0.5% trypsin for 6 min at 37 °C. Subsequently, the cells were centrifuged (7 min at 350 rpm), and the pellet was resuspended in annexin V binding buffer (1 ×) supplemented with 1.2 μg/mL of propidium iodide (PI) and 3 μM of annexin V-FITC (annexin V-FITC Apoptosis Staining/Detection Kit, Abcam) and left in the incubator at 37 °C for 15 min. The PI was used to stain necrotic cells, while the annexin V-FITC allowed the identification of apoptotic phenomena: the positivity to the annexin V-FITC marker is characteristic of the early apoptotic cells, while the double positivity to PI and annexin V-FITC is associated with late apoptosis. The percentages of viable (double negativity to both markers), necrotic, early apoptotic, and late apoptotic cells were analyzed by flow cytometry (FITC with λex = 488 nm and λem = 505–545 nm, ECD-A with λex = 488 nm and λem = 600–630 nm; Beckman Coulter CytoFLEX) using the CytoFLEX software.
Caspase-9 represents an initiator caspase, a cysteine-aspartic protease critical in triggering apoptotic signaling. Caspase-9 is active once integrated into the apoptosome, a large multimeric complex. The phosphorylation of caspase-9 inhibits the formation of the apoptosome. (49) The detection of the activated form of caspase-9 was performed by using the CaspGLOW fluorescein active caspase-9 staining kit (Biovision), following the manufacturer’s procedures, on “Control”, “Control + AMF”, “CM-LN1-L-SSH MNPs”, and “CM-LN1-L-SSH MNPs + AMF” experimental classes, 60 min after a single stimulation session with AMF. The fluorescein isothiocyanate (FITC)-conjugated LEHD-FMK, a specific ligand of caspase-9 activated form, was utilized for detection. Briefly, cells were incubated for 1 h with 150 μL of phenol red-free DMEM supplemented with 1 μL of the FITC-LEHD-FMK caspase-9 fluorescent dye. Cells were subsequently washed twice with the appropriate wash buffer provided by the manufacturer. The cells were detached by using 0.05% trypsin/EDTA, centrifuged, and finally resuspended in PBS for flow cytometer analysis (FITC with λex = 488 nm and λem = 505–545 nm). Fluorescence distributions were analyzed by using the CytoFLEX software. To identify the population of caspase-9 positive cells, the background fluorescence of nonstained cells was measured. Specifically, the highest fluorescence value of the nonstained controls was used to define the caspase-9 signal threshold: the population having a fluorescence intensity higher than the threshold was considered positive for the caspase-9 activation.

2.5.6. Migration Assay

The migration rate of PC-3 cells in four experimental classes (“Control”, “Control + AMF”, “CM-LN1-L-SSH MNPs”, and “CM-LN1-L-SSH MNPs + AMF”) was assessed using a scratch assay. The cells were seeded in 2-well culture insert systems (80209, Ibidi) at a seeding density of 1 × 105 cells/cm2 and incubated for 24 h. Then, they were treated with the plain medium as a control or with 250 μg/mL of CM-LN1-L-SSH MNPs for 24 h. After incubation, the culture insert was removed, and the cells were rinsed with PBS. The cultures were stained with 1 μM calcein (C3099, Invitrogen) for 15 min at 37 °C and then stimulated for 100 min with AMF as previously described. The gap between the cells (500 ± 100 μm) was imaged before starting AMF stimulation (t = 0 h) and after the stimulation (t = 24 h) by using a fluorescence microscope (Eclipse Ti, Nikon). The images were analyzed using ImageJ software (43) (version 1.53s) with the “Wound Healing” plug-in.

2.5.7. Proteomics

Samples of “Control”, “Control + AMF”, “CM-LN1-L-SSH MNPs”, and “CM-LN1-L-SSH MNPs + AMF” experimental classes were lysed, reduced, and alkylated in 50 μL of iST-LYSE buffer (PreOmics) for 10 min at 95 °C, centrifuged at 1000 rpm, and then treated as described in a previous work. (41) The resulting peptides were analyzed by a nano-ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) system using an Ultimate 3000 RSLC coupled to an Orbitrap Fusion Tribrid mass spectrometer (Thermo Scientific Instrument). Elution was performed with an EASY spray column (75 μm × 25 cm, 2 μm particle size, Thermo Scientific) at a flow rate of 400 nL/min using a nonlinear gradient of 2–30% solution B (80% acetonitrile and 20% H2O, 5% dimethyl sulfoxide, 0.1% formic acid) in 60 min. MS analysis was performed in DIA mode. Orbitrap detection was used for MS1 measurements at a resolving power of 120 K in a range between 375 and 1500 m/z and with a 300% AGC target. Advanced Peak Determination (APD) was enabled for MS1 measurements. High-field asymmetric waveform ion mobility spectrometry–compensation voltage (FAIMS CV) was set to −50 at standard resolution and with a total carrier gas flow of 1.5 L/min. Precursors were selected for data-independent fragmentation with an isolation window width of 25 m/z in 24 windows ranging from 380 to 980 m/z, with a 2 m/z overlap. Higher collisional dissociation (HCD) energy was set to 30%, and MS2 scans were acquired at a resolution of 15 k and 100% automatic gain control (AGC) target. All DIA raw files were processed with Spectronaut (version 16) (50) using a library-free approach (directDIA) under default settings.
The library was generated against the Uniprot Human database (release UP000005640_9606 February 2022). Carbamidomethylation was selected as a fixed modification, and methionine oxidation and N-terminal acetylation were selected as variable modifications. The false discovery rate (FDR) of peptide spectrum match (PSM) and peptide/protein groups was set to 0.01. For quantification, Precursor Filtering was set to Identified (Qvalue), and MS2 was chosen as quantity MS-level. The Protein Quant Pivot Report generated by Spectronaut was statistically evaluated using Perseus software (version 1.6.15.0). (51) GO enrichment specific for the prostate gland was obtained with the Web server ShinyGO (version 0.75).

2.6. Statistical Analysis

Data are expressed as mean ± standard deviation (SD). The numbers in parentheses of the numerical results obtained by the Pawley method in the XRD pattern simulation indicate the estimated standard deviation of the last significant digit. All cellular experiments were independently performed in triplicate. The results were analyzed with a one-way analysis of variance (ANOVA) through R software (version 4.2.0, R Foundation) followed by Tukey’s honest significant difference (HSD) posthoc test. “*” indicates the level of significance, corresponding to p < 0.05.

3. Results and Discussion

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3.1. Microstructural, Morphological, and Magnetic Characterization

Representative transmission electron microscopy (TEM) micrographs of SH, SHS, SS, and SSH MNPs are depicted in Figure 2a–d. The images reveal the cube-octahedral shape of SH nanoparticles (Figure 2a) with a mean diameter of 19.2 ± 1.2 nm (Figure S2a, Supporting Information). SHS TMNPs show similar shapes (Figure 2b) to the seeds, but with an increase in the average size (21.9 ± 0.8 nm) as a result of the coating process (Figure S2b, Supporting Information). Therefore, in the case of SS and SSH MNPs (Figure 2c–d), TEM images show a cube-octahedral morphology of particles. The size distribution histograms (Figure S2c–d, Supporting Information) show mean diameter values of 20.6 ± 0.5 nm (SS) and 23.0 ± 0.8 nm (SSH), confirming the growth of the second shell with approximately 1.5 nm thickness.

Figure 2

Figure 2. Representative BF-TEM images of (a) SH, (b) SHS, (c) SS, and (d) SSH MNPs. The insets represent the magnified TEM image of corresponding samples. (e) BF-TEM image and corresponding EFTEM elemental maps for the SSH sample. EFTEM mapping demonstrates the presence of Fe, Zn, Mn, and Co. (f) X-ray diffraction patterns of pristine samples (SH, SHS, SS, and SSH MNPs).

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To demonstrate the formation of the shell, we mapped the energy distribution of inelastically scattered electrons within the samples using EFTEM. The EFTEM elemental mapping of the SSH (Figure 2e) sample reveals the core–shell–shell nature of the nanoparticles. The results show a Fe-rich signal in the entire nanoparticle that predominantly belongs to the Fe3O4 core and the distribution of Mn, Zn, and Co atoms located in the Mn0.5Zn0.5Fe2O4 and CoFe2O4 shells, respectively. Similar data have been obtained for the magnetic core–shell architecture of SS MNPs (Figure S3, Supporting Information).
XRD patterns show that SH, SHS, SS, and SSH samples are highly crystalline, and no presence of a residual phase has been observed (Figure 2f). The main diffraction peaks were indexed to planes (220), (311), (222), (400), (422), (551), (440), (335), and (137) and matched to a face-centered cubic (fcc) unit cell of the spinel ferrite with the Fd3m space group (ICSD file no. 170911, PDF-4 Database).
The mean crystallite size of nanoparticles for each sample is slightly smaller than the average diameter obtained from TEM measurements (Table S1, Supporting Information) and may be explained by the existence of amorphous surface layers. (52) The lattice parameter (a) of the cubic unit cell for each sample (Table S1, Supporting Information) is very close to the magnetite (a = 8.380 Å). (31) We note a slight decrease in lattice constant for SHS and SSH samples compared to SH and SS samples, respectively, which can be attributed to the lattice mismatch between the seed and the outermost layer but that also may be due to lattice distortion or internal stress. (53)
The cube-octahedral morphology of SH and SHS MNPs, respectively, and their nanoscale arrangement is clearly perceived in SEM images (Figure S4a–b, Supporting Information). The images reveal a regular arrangement of SHS MNPs with an average edge length of 23 nm with smooth faces and cut edges (Figure S4b, Supporting Information). Comprehensive images of the morphology of SS and SSH MNPs are reported in Figure S4c–d, respectively (Supporting Information): a typical micrograph of the SSH nanoparticles shows well-defined faces, truncated edges, and an average edge length of 25 nm (Figure S4d, Supporting Information).
XPS was carried out to investigate the valence of the cations, the surface chemical composition of the pristine MNPs (SH, SHS, SS, SSH), and the magnetic shell formation onto the nanoparticles. The wide scan spectra (Figure S5, Supporting Information) display the typical photoemission peaks from the core levels of the elements composing the pristine MNPs (Fe, Mn, Co, Zn, O, and C), as well as their Auger peaks. High-resolution XPS scans on Fe 2p, Mn 2p, Co 2p, and Zn 2p peaks (Figure S6, Supporting Information) were collected and analyzed to extract detailed information on the chemical states of the metal cations.
Fitting of the transition metals’ XPS 2p spectra often requires particular care, as final-state effects might induce, in addition to usual spin–orbit coupling, shakeup and plasmon loss features, the so-called multiplet splittings, that need to be considered for a proper deconvolution of the peaks. (54−57) Specifically, multiplet splitting, which is present only for high spin species, requires that each of the two spin–orbital components of a 2p doublet is fitted with a certain number of subcomponents, whose structure in terms of shape, full-width-at-high-maximum (fwhm), binding energy (BE) position, and relative intensity depends on the chemical state of the element. The presence of multiple peaks can often be misinterpreted as differing oxidation states.
For these subcomponents, the parameters reported by Biesinger et al. (58) were used to fit Co 2p, Mn 2p, and Fe 2p regions, while Zn 2p does not present multiplet splitting effects but only the usual spin–orbital splitting into two components. (59) The fitting of the data, detailed in the Supporting Information, allowed us to identify the oxidation states of the cations in the pristine MNPs. In particular, the best fitting suggests that Co, Mn, and Zn are all present in +2 state, whereas Fe is mainly in +3 state, with a minor contribution from Fe(II). Moreover, we also estimated via XPS the elemental composition of the four pristine samples. The results are reported in Table 1. The experimental formula of SH, SS, SHS, and SSH MNPs was then calculated and compared to the expected composition of the external shells, as XPS probing depth is typically in the 5–10 nm range. (60)
Table 1. Elemental composition of Pristine Samples (SH, SHS, SS, and SSH MNPs) Determined by XPS
MNP sampleCo (%)Fe (%)Mn (%)Zn (%)O (%)Theor. formula (external shell)Exp. formula (external shell)
SH8.530.905.555.1Co0.5Zn0.5Fe2O4Co0.6Zn0.4Fe2.2O4
SHS0.932.15.70.460.8MnFe2O4Co0.06Zn0.03Mn0.4Fe2.1O4
SS022.810.312.953.9Mn0.5Zn0.5Fe2O4Mn0.8Zn1Fe1.7O4
SSH7.930.70.90.959.5CoFe2O4Mn0.06Zn0.06Co0.5Fe2.1O4
The obtained composition for the SH sample is very similar to the theoretical formula for the shell, suggesting its formation. The slight excess of Fe can be attributed to a fraction of the signal coming from the Fe3O4 core of the system. For the SHS system, a lower Mn/Fe atomic ratio than the expected value for the external shell has been observed. This result may be explained by the partial leaching of the Mn cations out of the shell layer. (31) Furthermore, the presence of Zn and Co signals, associated with the inner shell, suggests that the outer layer is very thin (thickness ≈ 1.7 nm). In the case of the SS sample, we note a lower amount of Fe and a higher amount of Zn and Mn with respect to the theoretical prediction, which may be attributed to the cationic diffusion mechanism or to the formation of an undesired Zn- and Mn-rich phase. Related to SSH nanoparticles, a lower amount of Co was detected in the external shell, but the presence of Mn and Zn atoms from the inner shell validates the formation of a very thin outer layer with the thickness under the sampling depth of the XPS beam (∼5 nm).
The XPS compositional analysis of pristine samples has been compared to the ICP-OES results (Table S2, Supporting Information), which should provide a closer estimation of the composition of the whole volume of the MNPs. The Fe content evaluated by ICP-OES is higher than that obtained by XPS for all the samples, as a result of the core–shell structure of the nanoparticles. Accordingly, the higher Co and Zn amounts (for sample SH) and Mn and Zn amounts (for sample SS) observed via XPS with respect to ICP support the shell formation around the magnetite core in both SH and SS samples. The XPS-ICP comparison is less straightforward in the core–shell–shell nanoparticles; however, the ICP and XPS results suggest that Mn is prevalently on the surface of the SHS system. Similar considerations are valid for SSH samplse, with Co prevalently located on the surface.
The magnetization curves of the pristine samples are presented in Figure 3a. The shape-anisotropic nanoparticles envisage a superparamagnetic behavior for SS and SSH samples and nonzero coercivity in the case of SH and SHS, respectively (inset of Figure 3a).

Figure 3

Figure 3. (a) Magnetic curves at room temperature of pristine samples (SH, SHS, SS, and SSH MNPs). The inset evidences the coercivity values. (b) Heating profile of ferrofluid samples (L-SH, L-SHS, L-SS, and L-SSH MNPs) exposed to AMF (f = 97.5 kHz, B = 20 mT, H = 15.9 kA/m; MNP concentration 5 mg/mL).

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In both cases (SSH and SHS), we noted a slight increase in specific saturation magnetization (Ms) for TMNPs compared to their bimagnetic counterparts (SS and SH samples, respectively; Table S3, Supporting Information). The specific magnetization of SSH MNPs (Ms = 77.1 Am2/kg) is higher than that of the SHS MNPs (Ms = 68.2 Am2/kg; Figure 3a). These results are different than those regarding bimagnetic nanoparticle systems (CoFe2O4@ MnFe2O4 and MnFe2O4@ CoFe2O4), where Ms is relatively similar. (61) We note that the physical phenomena ruling the magnatic properties of TMNPs are more complex than BMNPS and should be explored more extensively considering parameters such as shell thickness, nature of materials, or intermediate layer interdiffusion. (62) The magnetic remanence (Mr = 11.7 Am2/kg) of SHS MNPs is higher with respect to that of the SSH MNPs (Mr = 0.55 Am2/kg); moreover, the coercivity is notably different in the two systems of TMNPs. The magnetic curves show a 10-fold increase in the coercive field of SHS MNPs (Hc = 33.4 kA/m) with respect to that of SSH MNPs (Hc = 5.5 kA/m) nanoparticles. Kubisztal et al. have shown the anisotropy constant of CoFe2O4 nanoparticles (≈ 8 × 105 J m–3) is slightly different compared to Co0.5Zn0.5Fe2O4 (≈ 6 × 105 J m–3) nanoparticles. (63) The effective magnetic anisotropy and coercive field decrease with the increase of Zn concenteration in ZnxCo1–xFe2O4 due to the substitution of Co2+ ions of the octahedral site by the nonmagnetic Zn2+. Thus, taking into consideration a relatively similar thickness of inner and outer layers in each sample of our TMNPs, the difference in their coercivities might be related to the quality of the interfaces between the different materials. (56)
However, we further note a decrease in the coercivity of nanoparticles with SHS architecture with respect to their core–shell counterpart. Hence, the coercive field of SHS nanoparticles is 35% lower with respect to that of the SH system (Hc = 50.9 kA/m; Table S1, Supporting Information). A similar result was observed when MnFe2O4@CoFe2O4 nanoparticles have been coated with an additional shell comprising a soft magnetic phase, i.e., NiFe2O4. (19)
We evaluated the heating performance of L-SH, L-SHS, L-SS, and L-SSH MNPs using physical parameters within the range of clinical trials, i.e., AMF frequency f ≈ 100 kHz and field amplitude H = 2.5–18.0 kA/m. (64) From the calorimetric measurements of all the samples (Figure 3b), we obtained the highest heating ability (SAR = 69.6 W/g) in the case of SSH MNPs which is higher than the value of its corresponding bimagnetic core–shell seed (SAR = 45.1 W/g; Table S3, Supporting Information). Limiting the contributions of the external parameters, the ILP value demonstrated a higher conversion of magnetothermal energy for SSH MNPs (2.82 nH m2/kg; Table S3, Supporting Information) in comparison with the commercial magnetite Feridex (0.15 nH m2/kg). (65) The obtained value is about 19-fold higher than the FDA (Food and Drug Administration)-approved Feridex for biomedical applications, revealing the high potential application of SSH MNPs for MFH. A higher SAR was observed for the SHS system compared to the SH system (Table S3, Supporting Information): these data may be mainly described by the surface spin anisotropy of nanoparticles associated with the additional magnetic shell coating of BMNPs. (17) This layer could enhance the magnetic exchange coupling interactions at the trimagnetic shell–shell interface, resulting in SAR improvement, analogously to the bimagnetic core–shell nanoparticle behavior. (66)
Due to its highest heating efficiency among all studied samples, the SSH system was selected for further studies.

3.2. Cytocompatibility Evaluation

Figure S7 (Supporting Information) presents the WST-1 cell viability assay for L-SSH MNPs. The results demonstrated that L-SSH MNPs, up to 250 μg/mL, do not significantly affect the viability of both PC3 cells (Figure S7a) and human primary normal prostate cells (Figure S7b). At higher concentrations (500 μg/mL and 700 μg/mL), a significant decrease in cell metabolic activity was observed in both cell types. All the subsequent tests have been thus performed using the highest safe concentration of L-SSH nanoparticles (250 μg/mL).
Compared to other superparamagnetic nanostructures, L-SSH MNPs showed a biocompatibility level that is comparable to that of superparamagnetic iron oxide nanoparticles (SPIONs). Indeed, SPIONs showed a safe concentration of 100 μg/mL in SCC-9 cells derived from a primary tumor of the tongue when coated with human serum albumin (67) and of 400 μg/mL in the U87 glioblastoma-derived cell line when encapsulated in lipids. (18) Since SPIONs are considered safe nanomaterials and have been approved in clinics, the cytocompatibility observed for L-SSH is satisfying. However, the stability and safety of the nanoparticles should be confirmed in future experiments in vivo, where the degradation of the external layers of the nanostructure may expose cells to Co and thus induce toxicity.

3.3. Characterization of L-SSH, CM-L-SSH, LN1-L-SSH, and CM-LN1-L-SSH MNPs

This study aims at developing a novel strategy with an optimized heating efficiency for magnetic-mediated intracellular hyperthermia, along with improved stability, biocompatibility, and selective targeting of PCa cells, that potentially minimize systemic toxicity and maximize therapeutic benefit. Thus, the L-SSH system was further conjugated with LN1 cell-penetrating peptide (LN1-L-SSH MNPs), coated with cell membranes (CM-L-SSH MNPs) or functionalized with both CM and LN1 (CM-LN1-L-SSH MNPs). LN1 was preferred instead of antibodies, which commonly are much larger molecules, due to its high binding avidity and selectivity for PCa cells. (30) It is also known that it may induce apoptosis with high selectivity toward prostate cancer cells. (30) Cell-membrane-coated nanoparticles, on the other hand, can avoid protein adsorption and phagocytosis by the reticuloendothelial system (RES), extending their circulation time in vivo. (68)
The TEM micrographs reported in Figure 4a–c show the representative morphology of functionalized samples: LN1-L-SSH, CM-L-SSH, and CM-LN1-L-SSH MNPs, respectively. Figure 4a reveals the LN1-conjugated TMNPs, while Figure 4b–c confirm the lipid bilayer shell formation of approximately 3–5 nm thickness around the magnetic cores. This result is in agreement with other studies that report an outer thickness of about 5 nm of CM-coated Fe3O4. (69) In both cases, the micrographs of CM-L-SSH and CM-LN1-L-SSH MNPs present aggregates of magnetic nanoparticles with an inorganic core well encapsulated within the lipid coating.

Figure 4

Figure 4. BF-TEM micrographs of functionalized samples: (a) LN1-L-SSH MNPs, (b) negative-stained CM-L-SSH MNPs, and (c) negative-stained CM-LN1-L-SSH MNPs. DLS measurements: (d) hydrodynamic size distribution and (e) Z-potential before (L-SSH MNPs) and after functionalization (CM-L-SSH, CM-LN1-L-SSH, and CM-LN1-L-SSH MNPs).

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The DLS analysis of MNPs (Figure 4d) has shown an increasing trend in the mean hydrodynamic diameter from 293 ± 8 nm (L-SSH MNPs) to 334 ± 12 nm (CM-LN1-L-SSH MNPs) (Table S4; Supporting Information). The mean hydrodynamic diameter of LN1-L-SSH MNPs and CM-L-SSH MNPs is 304 ± 6 nm and 329 ± 6 nm, respectively. The polydispersity index (PDI) for each sample is reported in Table S4 (Supporting Information). After CM coating, a slight decrease of Z-potential (Figure 4e) from −12.4 ± 0.6 mV (L-SSH MNPs) to −13.9 ± 0.2 mV (CM-L-SSH MNPs) and to −14.7 ± 0.2 mV (CM-LN1-L-SSH MNPs) suggests an enhancement of colloidal stability (Table S4, Supporting Information). Other researchers claimed a similar range of Z-potential (−18 mV to – 13 mV) when myeloid-derived CM is used to coat Fe3O4 nanoparticles. (27) A slightly lower value of the Z-potential (−11.8 ± 0.7 mV) for LN1-L-SSH MNPs was finally determined (Table S4, Supporting Information).
The CM-LN1-L-SSH MNP stability has been evaluated mimicking various physiological conditions using PBS, DMEM, and 90% DMEM + 10% FBS (Figure S8, Supporting Information): the nanoparticles remain stable over 1 month and demonstrated a slightly lower stability than L-SSH MNPs.
TGA measurements were performed to quantify the amount of organic fraction grafted onto SSH MNPs as well as the magnetic phase present in the specimens (Figure S9, Supporting Information). The initial weight loss of about 1.4% occurring in the temperature range 80–100 °C may be assigned to the loss of water molecules adsorbed on the surface of the nanoparticles. The weight plot along increasing temperature of functionalized samples (CM-SSH, LN1-L-SSH, CM-LN1-L-SSH MNPs) suggests that the thermal degradation of the lipid component occurs in the range 190–280 °C. This temperature range matches very well with the endothermal decomposition of the short chain of amino acids. (70) The main peak observed on the derivative thermogram (DTG) of each sample ranges from 315 to 370 °C, and it is attributed to thermal degradation of the PEG component. The peak shift to lower temperatures in the first derivative plot may be due to competitive processes and various intramolecular reactions during the combustion of the cross-linked network (e.g., chain mobility during gelation), to the coverage density of PEG chains at the nanoparticle surface, or to the heat resistance of the PEG crystalline phase. (71,72) The organic mass loss of each sample during TGA (L-SSH MNPs: 6.7%, LN1-L-SSH MNPs: 7.4%, CM-L-SSH MNPs: 7.7%, CM-LN1-L-SSH MNPs: 9.3%; Table S4, Supporting Information) is in excellent agreement with the specific functionalization procedure, evidencing an efficient coating process of MNPs. As the ferrites are highly stable until 600 °C, the remaining mass represents the percentage of magnetic phase in the samples: 93.3% (L-SSH MNPs), 92.3% (CM-L-SSH MNPs), 92.6% (LN1-L-SSH MNPs), and 90.7% (CM-LN1-L-SSH MNPs) (Table S3, Supporting Information). The increasing trend of weight loss after 450 °C may be assigned to the adsorption of N2 molecules at the nanoparticle surface.
The BCA assay revealed that the amount of LN1 peptide in 1 mg/mL of LN1-L-SSH MNPs is 11.2 ± 3.6 μg/mL. The protein amount in 1 mg/mL of CM-L-SSH MNPs is instead 134.7 ± 10.2 μg/mL. Interestingly, 1 mg/mL of CM-LN1-L-SSH MNPs is characterized by a protein amount of 173.3 ± 1.2 μg/mL, a value higher than the simple sum of the values for LN1-L-SSH MNPs and CM-L-SSH MNPs: this increment can be attributed to the improved LN1 functionalization efficiency when used in combination with CM.
We therefore evaluated the magnetic behavior and heating efficiency of CM-LN1-L-SSH MNPs (Figure S10a, Supporting Information). The results show that CM-LN1-L-SSH MNPs did not change the superparamagnetic behavior (Hc = 6.3 kA/m), whereas the saturation magnetization (MS = 66.2 kA/m2) is lower than that of the pristine sample (MS = 77.1 kA/m2), mainly because of the organic coating. Therefore, the magnetothermal experiment demonstrated a decrease of SAR from 69.6 W/g (L-SSH) to 61.2 W/g (CM-LN1-L-SSH MNPs; Figure S10b, Supporting Information).

3.4. Cellular Internalization

Figure 5a depicts representative images of performed analyses, and it shows F-actin (in red), MNPs (in green), nuclei (in blue), and merged signals. An increase in nanoparticle uptake in the case of LN1-L-SSH and CM-LN1-L-SSH MNPs, with respect to the other experimental classes (L-SSH and CM-L-SSH MNPs), can be appreciated. The localization of MNPs is mainly perinuclear.

Figure 5

Figure 5. (a) Representative confocal images of PC-3 cultures incubated for 72 h with 250 μg/mL of MNPs (L-SSH, LN1-L-SSH, CM-L-SSH, and CM-LN1-L-SSH MNPs). F-actin in red, MNPs in green, and nuclei in blue. (b) ICP-OES elemental quantification of Fe (green), Zn (pink), Mn (gray), and Co (yellow) in PC-3 cells treated with the different MNPs.

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The quantitative ICP-OES analysis confirmed the qualitative results obtained by confocal imaging (Figure 5b). A significant increase in cell uptake was found when using LN1-L-SSH nanoparticles compared to L-SSH MNPs (1.2-fold), while the highest uptake efficiency of nanoparticles in PC-3 cells (particularly, in terms of Fe) was observed when using CM-LN1-L-SSH MNPs (2.4-fold compared to L-SSH MNPs).
This result demonstrates that combining the homotypic CM coating approach with LN1 functionalization allows for enhanced targeting. The improved uptake may be attributed not only to the combination of the two targeting approaches but also to the higher amount of LN1 present in the CM-LN1-L-SSH system compared to LN1-L-SSH MNPs. For this reason, CM-LN1-L-SSH MNPs were used for all the subsequent experiments.

3.5. Proliferation, Apoptosis, and Necrosis in Response to Magnetothermal Treatment

The effects of hyperthermia treatment following CM-LN1-L-SSH MNP administration have been evaluated. Figure 6a shows the CLSM analysis of the expression of the Ki-67 proliferation marker in the following experimental classes: “Control”, “Control + AMF”, “CM-LN1-L-SSH MNPs”, and “CM-LN1-L-SSH MNPs + AMF”.

Figure 6

Figure 6. (a) Representative confocal laser scanning microscopy imaging of Ki-67 expression in PC-3 cells in the considered experimental classes. Nuclei in blue, Ki-67 in green, and F-actin in red. (b) In red, % of cells normalized to controls. In green, % of Ki-67-positive cells (Ki-67+).

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To locally investigate the temperature reached by the nanoparticles at the cellular level, the CM-LN1-L-SSH MNPs were stained with the temperature-sensitive lipophilic DiI dye, and CLSM time-lapse imaging was carried out (Figure S11a, Supporting Information). The fluorescence intensity of the CM-LN1-L-SSH MNPs was monitored in real-time during AMF stimulation (Figure S11b). The decrease in fluorescence intensity induced by CM-LN1-L-SSH MNPs + AMF can be attributed to an increase in temperature as described by the ΔF/F0 = −0.0224·ΔT equation. (49) The T graph during magnetothermal stimulation is shown in Figure S11c, suggesting that CM-LN1-L-SSH MNPs reach T > 40 °C in the cells upon AMF stimulation.
We observed a significant decrease in cell density in response to the “CM-LN1-L-SSH MNPs + AMF” treatment (36.9 ± 21.4%) compared to the other experimental classes (100.0 ± 15.3% for “Control”, 92.5 ± 4.4% for “Control + AMF”, 86.1 ± 10.7% for “CM-LN1-L-SSH MNPs”; Figure 6b). Also, a lower Ki-67 expression signal intensity (in green) was observed in the “CM-LN1-L-SSH MNPs + AMF” class compared to the other experimental groups (Figure 6a). However, despite the lower signal intensity, a similar % of Ki-67+ cells (Figure 6b) was found in the “CM-LN1-L-SSH MNPs + AMF” treatment (24.0 ± 4.7%) compared to “Control” (27.2 ± 8.1%), “Control + AMF” (24.8 ± 6.9%), and “CM-LN1-L-SSH MNPs” (27.0 ± 4.7%). Considering that the same cell number was seeded in the different experimental classes, the result indicating a lower number of cells upon magnetothermal stimulation can be attributed to cell death and detachment phenomena, and it is in line with the WST-1 assay (Figure S12, Supporting Information), where a remarkable decrease in cell viability was detected in response to the “CM-LN1-L-SSH MNPs + AMF” treatment (54.4 ± 2.3%) but not in the case of “Control + AMF” (90.4 ± 1.6%) and of “CM-LN1-L-SSH MNPs” (103.3 ± 11.1%) treatment. Altogether, the immunofluorescence and WST-1 analyses indicate that the chronic magnetothermal stimulation induced by the AMF treatment in the presence of CM-LN1-L-SSH MNPs produces a significant cytotoxic effect, remarkably reducing the number of cells without using any chemotherapic drug. Also, the stimulation approach has been carried out at safe nanoparticle concentrations and AMF doses. Indeed, no significant effect on cell density was found in the “Control + AMF” and “CM-LN1-L-SSH MNPs” experimental conditions. This chemotherapy-free approach allows us to localize the anticancer treatment only where nanoparticles are accumulated and AMF is applied, thus potentially limiting the side effects of anticancer therapy on healthy tissues.
Concerning the anticancer mechanisms of the “CM-LN1-L-SSH MNPs + AMF” treatment, the decrease in the Ki-67 signal is evidence of decreased proliferation. (73) The presence of a lower Ki-67 expression is attributed to the slow yet progressive degradation of this marker during quiescence, while the level of decrease depends on the time that cells remained in the G0 cycle phase. The lower amount of this marker, therefore, indicates that the cells upon “CM-LN1-L-SSH MNPs + AMF” treatment are not in the S, G2, and M proliferation phases, yet exit from the cell cycle.
Compared to other magnetic nanoplatforms in the literature, the in vitro anticancer efficacy of CM-LN1-L-SSH MNPs is relatively high. Some authors reported the use of highly pure magnetosome for the treatment of PC3 cancer cells by inductive heating: (74) the treatment with citric-acid-functionalized magnetosome (M-CA) and AMF (f = 195 kHz, B = 42 mT) was able to reduce by 35.5% the cell viability with respect to the treatment with only M-CA. In another example, the cell viability of BV2 cells decreased by approximately 30% after magnetic hyperthermia treatment induced by poly(acrylic acid)-coated iron oxide nanoparticles and AMF (f = 560 kHz, H = 23.9 kA/m). (75)
An interesting finding of Calatayud et al. provides that cell viability can still decrease many hours after magnetic treatment due to progressive cell death. (66) For this reason, apoptosis and necrosis have been investigated. Flow cytometer analysis of early apoptotic, late apoptotic, and necrotic cells (Figure 7) has been carried out to investigate if cell death was involved in the anticancer mechanism induced by the “CM-LN1-L-SSH MNPs + AMF” treatment.

Figure 7

Figure 7. Flow cytometry analysis of apoptosis/necrosis: (a) representative flow cytometer scatter plots of propidium iodide vs annexin V-FITC. The populations of healthy, early apoptotic, late apoptotic, and necrotic cells have been highlighted in black, green, blue, and red, respectively. (b) Quantitative evaluation.

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In Figure 7a, representative flow cytometer scatter plots of propidium iodide vs annexin V-FITC are shown, and the populations of healthy, early apoptotic, late apoptotic, and necrotic cells have been highlighted in black, green, blue, and red, respectively. Figure 7b reports the quantitative evaluation of the obtained data. The “CM-LN1-L-SSH MNPs + AMF” treatment induced a significant decrease of the healthy cells (79.8 ± 3.6%) compared to “Control” (96.1 ± 2.1%; p < 0.05), “Control + AMF” (96.6 ± 2.6%), and “CM-LN1-L-SSH MNPs” (93.4 ± 1.3%) groups. No remarkable effect on healthy cells was observed in “Control + AMF” and “CM-LN1-L-SSH MNPs” groups compared to “Control”, therefore confirming that the single stimulation does not have harmful effects on PC-3 cells. The decrease of healthy cells in response to magnetothermal stimulation can be attributed mainly to apoptotic phenomena (9.5 ± 3.6% of early apoptotic and 7.9 ± 1.1% of late apoptotic cells in the “CM-LN1-L-SSH MNPs + AMF” group) and, secondarily, to necrotic events (2.7 ± 1.0% in the “CM-LN1-L-SSH MNPs + AMF” group).
We have to highlight that the stimulation time is sufficient to increase the temperature of the nanoparticles in the cells from room temperature to above 40 °C, in the appropriate range of temperatures used for hyperthermia (40–43 °C). (76) These results indicate that the magnetothermal treatment affects cancer cell viability by both reducing proliferation and inducing cell death primarily through apoptosis. Apoptosis is a programmed cell death that does not induce tissue damage or inflammation. For this reason, traditionally, anticancer treatments inducing apoptosis (e.g., hyperthermia) are preferred with respect to necrosis (e.g., thermal ablation). However, cancer cells can avoid such types of cell death by blocking apoptotic signaling. Overexpression of chaperones, such as heat-shock protein 70 and 27 (hsp70 and hsp27), can inhibit caspase-dependent and caspase-independent apoptotic pathways. (77,78) These defense mechanisms are normally triggered by cells in response to stress and are particularly developed in cancer cells. Despite the protection offered by chaperones, however, physical treatments (e.g., with electric and thermal cues) are capable of activating apoptotic pathways in cancer cells. In the specific case of thermal stimuli, the temperature of about 42 °C is known to induce apoptosis through the activation of caspases. (79) Specifically, caspase-9 is highly activated after heat, is downstream of the activation cascade, and represents a good marker of the apoptotic trigger. (69) For these reasons, experiments have been conducted to analyze the expression of hsp70 and the activation of caspase-9 in PC-3 cells under MNP-mediated hyperthermia.

3.6. Biochemical Pathways Activated in Response to Magnetothermal Treatment

The immunofluorescence analysis of the hsp70 expression in “Control”, “Control + AMF”, “CM-LN1-L-SSH MNPs”, and “CM-LN1-L-SSH MNPs + AMF” experimental classes, 60 min after a single stimulation session with AMF, is shown in Figure 8.

Figure 8

Figure 8. (a) Expression of hsp70 in PC-3 cells upon magnetothermal stimulation: representative confocal laser scanning microscopy imaging (nuclei in blue, hsp70 in green, F-actin in red). (b) Average intensity of the hsp70 signal in the cells for each experimental condition (* p < 0.05).

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CLSM imaging of the hsp70 expression (in green), F-actin (in red), nuclei (in blue), and the merged signals is presented in Figure 8a. Qualitatively, the low number of cells in the “CM-LN1-L-SSH MNPs + AMF” group that survived to magnetic hyperthermia treatment display a higher hsp70 signal intensity compared to the other experimental classes. In Figure 8b, the graph reports the average intensities of the hsp70 signal in the different experimental classes with respect to “Control”. The hsp70 signal intensity upon magnetothermal treatment (“CM-LN1-L-SSH MNPs + AMF”; 187.2 ± 17.9%) is significantly higher compared to the other experimental classes (100.0 ± 14.2% for “Control”, 115.3 ± 18.1% for “Control + AMF”; 115.3 ± 16.7% for “CM-LN1-L-SSH MNPs”). The increase in hsp70 expression is a well-defined indicator of mild heat stress and is associated with the temperature increase over time. (34) The observed increase in hsp70 expression can be therefore associated with the cell response to the heat stimulation induced by the AMF in the presence of magnetic nanoparticles. Hsp70 is known to be able to protect cancer cells from apoptosis. The observed enhanced expression of this chaperone in the surviving cells may have reduced the probability to incur heat-dependent apoptotic death. A remarkable hsp70 activation was also observed in ovarian cells treated with magnetic fluid hyperthermia, and different strategies have been tested to inhibit hsp70 expression and function, including siRNA and the 2-phenylethynesulfonamide (PES) inhibitor of hsp70 activity: (80) these approaches resulted in reduced cell viability in response to the magnetothermal treatment. A synergic combination of magnetic hyperthermia and drugs inhibiting hsp70 can therefore be proposed in future works for enhancing the magnetothermal treatment in prostate cancer as well.
The activation of the caspase-9 apoptotic pathway was investigated in response to the acute stimulation with magnetic hyperthermia (“CM-LN1-L-SSH MNPs + AMF”), and results have been compared to the “Control + AMF”, “CM-LN1-L-SSH MNPs”, and “CM-LN1-L-SSH MNPs + AMF” experimental classes (Figure 9).

Figure 9

Figure 9. Activation of the caspase-9 apoptotic pathway upon acute stimulation with magnetic hyperthermia (“CM-LN1-L-SSH MNPs + AMF”). (a) Representative distributions of the cell fluorescent signal emission. Caspase-9-negative (−) and -positive (+) cells are highlighted in light blue and light red, respectively. (b) Quantitative evaluation of flow cytometry data for each experimental condition (* p < 0.05).

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Caspase-9 is activated by recruitment and dimerization within the Apaf-1 apoptosome. In turn, once activated, caspase-9 can trigger caspases-3, – 6, and −7 of the apoptotic signal. (37) The activated form of caspase-9 has been detected by flow cytometry using the FITC-conjugated LEHD-FMK. In Figure 9a, representative graphs with the fluorescence emission distributions of the four experimental groups are presented; in Figure 9b, the graph reports the % of caspase-9+ cells. A significant increase of caspase-9+ cells has been observed in the “CM-LN1-L-SSH MNPs + AMF” group (10.1 ± 0.8%) with respect to “Control” (3.0 ± 0.4%), “Control + AMF” (3.7 ± 1.3%), and “CM-LN1-L-SSH MNPs” (3.3 ± 0.9%) groups. The reported 3.4-folds increase in the caspase-9 activated form in “CM-LN1-L-SSH MNPs + AMF” compared to “Control” after a single magnetothermal treatment is in agreement with the enhanced apoptotic levels previously reported, suggesting that the triggering of the apoptotic pathway in response to magnetic hyperthermia can be associated with the activation of caspase-9.

3.7. Cell Migration upon Acute Magnetothermal Stimulation

The cell migration ability of PC-3 cells was analyzed in vitro in the presence of CM-LN1-L-SSH MNPs and AMF stimulation (Figure 10). The representative fluorescence images of the migration area before and after the stimulation (t = 0 h and t = 24 h) are shown in Figure 10a, while the percentage of gap size is reported in Figure 10b. The cells treated with CM-LN1-L-SSH MNPs in the presence or absence of AMF stimulation showed a significant reduction in PC-3 cell migration with respect to the control cultures. The gap size increased to 30.9 ± 9.9% and 69.9 ± 20.2% in CM-LN1-L-SSH MNP-treated cells in the presence and absence of AMF stimulation, respectively, while the gap size was 11.2 ± 10.3% and 3.8 ± 3.6% in control cultures. In addition, the CM-LN1-SSH MNP-treated cells showed a significant increase in gap size when AMF was applied, if compared to the only CM-LN1-SSH MNP-treated cultures.

Figure 10

Figure 10. Cell migration upon acute magnetothermal stimulation. (a) Representative images of PC-3 cells stained with calcein at t = 0 h and t = 24 h of cell migration. (b) % of gap size measured in each experimental class (* p < 0.05).

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Although metastatic cascade is a complex process in cancer progression, cell migration is a pivotal step for the initiation of long-distance metastasis. (81) Here, the PC-3 cell migration was evaluated by in vitro scratch assay providing information about the migration capacity over time. Some studies suggested that iron oxide nanoparticles restrict the migration of cells by inhibiting the activity of the actin cytoskeleton and destroying microtubule networks, resulting in loss of focal adhesion. (82,83) In another study, SPIONs decreased the migration of glioblastoma cells by inhibiting the invasion capability of cells via mannose-6-phosphate (M6P) receptors. (84)
Hyperthermia is capable of adversely affecting cell membrane fluidity and stability as well as altering the function of transmembrane proteins and cell surface receptor expression. (85) Notably, tumor cells are more sensitive to temperature increment than normal cells, which makes hyperthermia an attractive tool for antitumor therapy. (86) In our study, PC-3 cells reacted to the CM-LN1-L-SSH MNP-mediated hyperthermia by overexpressing the hsp70 protein: recently, a study showed that the overexpression of hsp70 proteins in A549 lung cancer cells leads to an inhibition of TGF-β signaling, which plays a significant role in cell migration reduction, (87) thus corroborating our findings.

3.8. Proteomic and Gene ontology (GO) Analysis

Proteomic and gene ontology (GO) analyses have been performed to detect the differently represented proteins (DRP) and pathways involved in the magnetothermal treatment (Figure 11). The proteomic analyses were carried out for “Control”, “Control + AMF”, “CM-LN1-L-SSH MNPs”, and “CM-LN1-L-SSH MNPs + AMF” experimental classes.

Figure 11

Figure 11. Proteomic analysis: (a) principal component analysis (PCA) for 4 independent experiments in “Control” (blue cross), “Control + AMF” (orange square), “CM-LN1-L-SSH MNPs” (magenta circles), and “CM-LN1-L-SSH MNPs + AMF” (rhombuses in olive green color) treatments; (b) volcano plot and GO keywords regarding the “Control + AMF vs Control”, “CM-LN1-L-SSH MNPs vs Control”, and “CM-LN1-L-SSH MNPs + AMF vs Control” comparisons; upregulated and downregulated pathways are highlighted in green and red, respectively.

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The principal component analysis (PCA) of the first 2 components (accounting for 35.4% and 12.7% of the variance) is shown in Figure 11a (the symbols represent the four independent experiments for each experimental class). The component pattern plot of the PCA highlighted as “CM-LN1-L-SSH MNPs + AMF” represents the treatment with the most significant phenotypic variation compared to “Control”. This result demonstrates the synergic effect of the AMF stimulation and the treatment with CM-LN1-L-SSH MNPs. The “Control + AMF” and “CM-LN1-L-SSH MNPs” groups are positioned near the “Control” in the component pattern plot, demonstrating the safety of the single stimuli used for magnetic hyperthermia, in line with the previous results on cell viability, Ki-67 expression, apoptosis/necrosis, hsp70 expression, and caspase-9 expression.
Figure 11b shows the volcano plots and the associated GO keywords of the 3 comparisons: “Control + AMF vs Control”, “CM-LN1-L-SSH MNPs vs Control”, and “CM-LN1-L-SSH MNPs + AMF vs Control”. The signaling pathway upregulation and downregulation compared to “Control” is, respectively, highlighted in green and red. In line with the results of the PCA, the comparison showing the higher number of DRP is “CM-LN1-L-SSH MNPs + AMF vs Control” (DRP = 2408 of 5908 detected proteins). The “CM-LN1-L-SSH MNPs vs Control” comparison showed a remarkably lower number of DRP (DRP = 127) compared to “CM-LN1-L-SSH MNPs + AMF vs Control”. “Control + AMF vs Control” comparisons did not show any DRP, highlighting the scarce interference that the magnetic field has at these frequencies and intensities. Since no DRP was found in “Control + AMF vs Control” comparison, no GO keywords have been highlighted for this comparison.
Significant GO terms involved in the “CM-LN1-L-SSH MNPs” treatment are “Cellular response to external stimulus”, “Negative regulation of autophagy”, “Extracellular matrix organization”, and “Extracellular encapsulating structure organization”. The upregulation of the “Cellular response to external stimulus” indicates that the PC-3 cells recognize the presence of the nanoparticles and activate a cellular response to this stimulus. Considering that a similar number of DRPs involved in the negative (DRP = 10) and positive (DRP = 12) regulation of the extrinsic apoptotic signaling pathways have been expressed in the “CM-LN1-L-SSH MNPs” group, the cell response to the external stimulus may not involve apoptosis. This result is in line with the apoptosis/necrosis evaluation. The “Negative regulation of autophagy” can be associated with the accumulation of nanomaterial and undesirable components in the cells. (88) Instead, the “Extracellular structure organization”, “Extracellular matrix organization”, and “Extracellular encapsulating structure organization” are associated with the migration and invasion of cancer cells in the extracellular matrix and their upregulation, (89) and they may explain the decreased migration levels in the “CM-LN1-L-SSH MNPs” treatment.
Downregulated GO terms in the “CM-LN1-L-SSH MNPs + AMF” group are “Cytoskeleton organization”, “Actin cytoskeleton organization”, “Cell cycle”, “Cell division”, and “Protein phosphorylation”, while upregulated GO terms include “Intracellular transport”. The downregulation of “Cytoskeleton organization” and of “Actin cytoskeleton organization” is associated with the decreased migration observed in response to the “CM-LN1-L-SSH MNPs + AMF” treatment. Considering that “Protein phosphorylation” is the most common mechanism of cell signaling regulation, its downregulation can be attributed to the impaired activity of dying cells, in the late phases of apoptosis and necrosis. (90) The downregulation of “Cell cycle” and “Cell division” signaling pathways is a key requirement for the development of efficient anticancer treatment. Indeed, the scarce proliferation of the cancer cells that survived to the “CM-LN1-L-SSH MNPs + AMF” magnetothermal treatment may limit cancer aggressiveness and the probability of recurrence. The upregulation of the “Intracellular transport” is associated with elevated apoptotic levels and is due to the elevation of adenosine triphosphate (ATP) concentration in apoptotic cells. (91) Indeed, intracellular transport is known to be accelerated during apoptosis (especially during the early phases): the increased intracellular transport is known to be critical for apoptotic mechanisms, and apoptosis can be delayed if it is regulated back to the normal level. (81)
The complete list of the GO terms related to the “CM-LN1-L-SSH MNPs” and “CM-LN1-L-SSH MNPs + AMF” groups has been reported as Supporting Information in Figure S13 and Figure S14, respectively (the number of genes, the fold enrichment, and the false discovery rate related to each GO term have been specified).

4. Conclusions

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We reported on a novel class of magnetic core–shell–shell nanoparticles (i.e., trimagnetic nanoparticles) that consist of soft–soft–hard (SSH) nanostructure with enhanced heating ability (i.e., specific absorption rate) upon alternating magnetic field stimulation. We demonstrated that cell-membrane-coated and cell-penetrating peptide-conjugated nanoparticles improve the targeting of prostate cancer cells in vitro. We evidenced that the enhanced magnetothermal conversion efficiency of this system induced cell death mainly through the apoptosis process. The chronic magnetic hyperthermia treatment induced cell death through the caspase-9 pathway and significantly downregulated the cell cycle progression and cell-division-related pathways. Moreover, a decreased migration level has been observed in response to the magnetothermal treatment. Since the propensity of cancer cells to migrate correlates with tumor invasiveness, (92) the proposed stimulation approach may have an important function in vivo in reducing the ability of tumor cells to invade surrounding tissues. The reduced migration in stimulated cells may be attributed to the significant downregulation of the cytoskeleton organization pathways observed with proteomics and GO analysis.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsami.3c07248.

  • Fourteen figures, four tables, and an accurate description of XPS analysis (PDF)

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Author Information

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  • Corresponding Authors
  • Authors
    • Carlotta Pucci - Istituto Italiano di Tecnologia, Smart Bio-Interfaces, Viale Rinaldo Piaggio 34, 56025 Pontedera, Italy
    • Özlem Şen - Istituto Italiano di Tecnologia, Smart Bio-Interfaces, Viale Rinaldo Piaggio 34, 56025 Pontedera, Italy
    • Melis Emanet - Istituto Italiano di Tecnologia, Smart Bio-Interfaces, Viale Rinaldo Piaggio 34, 56025 Pontedera, Italy
    • Daniele De Pasquale - Istituto Italiano di Tecnologia, Smart Bio-Interfaces, Viale Rinaldo Piaggio 34, 56025 Pontedera, Italy
    • Alessio Carmignani - Istituto Italiano di Tecnologia, Smart Bio-Interfaces, Viale Rinaldo Piaggio 34, 56025 Pontedera, Italy;  Sant’Anna School of Advanced Studies, The Biorobotics Institute, Viale Rinaldo Piaggio 34, 56025 Pontedera, Italy;  Orcidhttps://orcid.org/0000-0002-6316-3478
    • Andrea Petretto - IRCCS Istituto Giannina Gaslini, Core Facilities-Clinical Proteomics and Metabolomics, Via Gerolamo Gaslini 5, 16147 Genova, Italy
    • Martina Bartolucci - IRCCS Istituto Giannina Gaslini, Core Facilities-Clinical Proteomics and Metabolomics, Via Gerolamo Gaslini 5, 16147 Genova, Italy
    • Simone Lauciello - Istituto Italiano di Tecnologia, Electron Microscopy Facility, Via Morego 30, 16163 Genova, Italy
    • Rosaria Brescia - Istituto Italiano di Tecnologia, Electron Microscopy Facility, Via Morego 30, 16163 Genova, Italy;  Orcidhttps://orcid.org/0000-0003-0607-0627
    • Francesco de Boni - Istituto Italiano di Tecnologia, Materials Characterization Facility, Via Morego 30, 16163 Genova, Italy
    • Mirko Prato - Istituto Italiano di Tecnologia, Materials Characterization Facility, Via Morego 30, 16163 Genova, Italy;  Orcidhttps://orcid.org/0000-0002-2188-8059
    • Sergio Marras - Istituto Italiano di Tecnologia, Materials Characterization Facility, Via Morego 30, 16163 Genova, Italy
    • Filippo Drago - Istituto Italiano di Tecnologia, Electron Microscopy Facility, Via Morego 30, 16163 Genova, Italy
    • Mohaned Hammad - University of Duisburg-Essen, Particle Science and Technology - Institute for Combustion and Gas Dynamics (IVG-PST), Carl-Benz Strasse 199, 47057 Duisburg, Germany
    • Doris Segets - University of Duisburg-Essen, Particle Science and Technology - Institute for Combustion and Gas Dynamics (IVG-PST), Carl-Benz Strasse 199, 47057 Duisburg, Germany;  Orcidhttps://orcid.org/0000-0003-3102-2934
  • Author Contributions

    V.N.: Conceptualization, Methodology, Formal analysis, Validation, Investigation, Writing - Original Draft, Visualization. A.M.: Conceptualization, Methodology, Formal analysis, Investigation, Writing - Original Draft. C.P.: Methodology, Validation. O.S. and M.E.: Methodology, Formal analysis, Investigation. D.P. and A.C.: Investigation. A.P., M.B., S.L., F.B., M.P., S.M., and F.D.: Validation, Investigation. R.B.: Validation, Investigation, Writing. M.H. and D.S.: Investigation, Resources. G.C.: Conceptualization, Methodology, Investigation, Resources, Writing - Review & Editing, Supervision, Project administration, Funding acquisition.

  • Funding

    This project has received funding from AIRC and the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 800924.

  • Notes
    This work reflects only the author’s view, and the funding agencies are not responsible for any use that may be made of the information it contains.
    The authors declare no competing financial interest.

Acknowledgments

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The authors kindly thank Giammarino Pugliese and Doriana Debellis for their technical support in TGA and in the negative staining preparation for BF-TEM imaging, respectively.

References

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This article references 92 other publications.

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    Localized magnetic hyperthermia (LMHT) cancer therapy is a much-anticipated technique along with immunotherapy. LMHT can be used as an independent or adjunct therapy to increase the efficacy of radiation and chemotherapy. The superparamagnetic nanoparticles (SPNPs) create LMHT by the electron magnetic spin relaxation (EMR) mechanism in nanocolloids. Magnetic nanoparticles of MgFe2O4 doped with different concns. of Ca2+ ions were designed to find sp. heating efficiency in magnetic hyperthermia (MHT) for applications in cancer therapy. Ca2+-substituted MgFe2O4 (CaxMg1-xFe2O4, x = 0.1, 0.3, and 0.5) nanoparticles with cubic spinel shapes and significant sizes were synthesized using high b.p. org. solvents. The heating efficiency or specific loss power (SLP) was detd. using a calorimetric method under various amplitudes of the magnetic field. The best shape with a particular size range for nanoparticles dispersed in deionized (DI) water carriers producing the optimum heating efficiency was specified. The CaxMg1-xFe2O4 (x = 0.1, 0.3, and 0.5) nanoparticles were investigated for in vitro cytotoxicity in normal cells (the mouse muscle fibroblast cell line BLO-11 and the mouse embryonic fibroblast cell line NIH 3T3) and human cancer cells (breast cancer cell line MDA-MB-23 and prostate cancer cell line PC-3) in terms of cell viability. The excellent heating efficiency and biocompatibility along with the less cell cytotoxicity of Ca2+-substituted MgFe2O4 nanoparticles were obsd. These outcomes propose that MgFe2O4 nanoparticles doped with Ca2+ ions are appropriate for biomedical applications, esp. for MHT cancer therapy.
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    Kossatz, S.; Grandke, J.; Couleaud, P.; Latorre, A.; Aires, A.; Crosbie-Staunton, K.; Ludwig, R.; Dähring, H.; Ettelt, V.; Lazaro-Carrillo, A.; Calero, M.; Sader, M.; Courty, J.; Volkov, Y.; Prina-Mello, A.; Villanueva, A.; Somoza, C.; Cortajarena, A. L.; Miranda, R.; Hilger, I. Efficient Treatment of Breast Cancer Xenografts with Multifunctionalized Iron Oxide Nanoparticles Combining Magnetic Hyperthermia and Anti-Cancer Drug Delivery. Breast Cancer Res. 2015, 17 (1), 66,  DOI: 10.1186/s13058-015-0576-1
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    Breast cancer research : BCR (2015), 17 (), 66 ISSN:.
    INTRODUCTION: Tumor cells can effectively be killed by heat, e.g. by using magnetic hyperthermia. The main challenge in the field, however, is the generation of therapeutic temperatures selectively in the whole tumor region. We aimed to improve magnetic hyperthermia of breast cancer by using innovative nanoparticles which display a high heating potential and are functionalized with a cell internalization and a chemotherapeutic agent to increase cell death. METHODS: The superparamagnetic iron oxide nanoparticles (MF66) were electrostatically functionalized with either Nucant multivalent pseudopeptide (N6L; MF66-N6L), doxorubicin (DOX; MF66-DOX) or both (MF66-N6LDOX). Their cytotoxic potential was assessed in a breast adenocarcinoma cell line MDA-MB-231. Therapeutic efficacy was analyzed on subcutaneous MDA-MB-231 tumor bearing female athymic nude mice. RESULTS: All nanoparticle variants showed an excellent heating potential around 500 W/g Fe in the alternating magnetic field (AMF, conditions: H=15.4 kA/m, f=435 kHz). We could show a gradual inter- and intracellular release of the ligands, and nanoparticle uptake in cells was increased by the N6L functionalization. MF66-DOX and MF66-N6LDOX in combination with hyperthermia were more cytotoxic to breast cancer cells than the respective free ligands. We observed a substantial tumor growth inhibition (to 40% of the initial tumor volume, complete tumor regression in many cases) after intratumoral injection of the nanoparticles in vivo. The proliferative activity of the remaining tumor tissue was distinctly reduced. CONCLUSION: The therapeutic effects of breast cancer magnetic hyperthermia could be strongly enhanced by the combination of MF66 functionalized with N6L and DOX and magnetic hyperthermia. Our approach combines two ways of tumor cell killing (magnetic hyperthermia and chemotherapy) and represents a straightforward strategy for translation into the clinical practice when injecting nanoparticles intratumorally.
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    Beola, L.; Grazú, V.; Fernández-Afonso, Y.; Fratila, R. M.; De Las Heras, M.; De La Fuente, J. M.; Gutiérrez, L.; Asín, L. Critical Parameters to Improve Pancreatic Cancer Treatment Using Magnetic Hyperthermia: Field Conditions, Immune Response, and Particle Biodistribution. ACS Appl. Mater. Interfaces 2021, 13 (11), 12982– 12996,  DOI: 10.1021/acsami.1c02338
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    ACS Applied Materials & Interfaces (2021), 13 (11), 12982-12996CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
    Magnetic hyperthermia (MH) was used to treat a murine model of pancreatic cancer. This type of cancer is generally characterized by the presence of dense stroma that acts as a barrier for chemotherapeutic treatments. Several alternating magnetic field (AMF) conditions were evaluated using three-dimensional (3D) cell culture models loaded with magnetic nanoparticles (MNPs) to det. which conditions were producing a strong effect on the cell viability. Once the optimal AMF conditions were selected, in vivo expts. were carried out using similar frequency and field amplitude parameters. A marker of the immune response activation, calreticulin (CALR), was evaluated in cells from a xenograft tumor model after the MH treatment. Moreover, the distribution of nanoparticles within the tumor tissue was assessed by histol. anal. of tumor sections, observing that the exposure to the alternating magnetic field resulted in the migration of particles toward the inner parts of the tumor. Finally, a relationship between an inadequate body biodistribution of the particles after their intratumoral injection and a significant decrease in the effectiveness of the MH treatment was found. Animals in which most of the particles remained in the tumor area after injection showed higher redns. in the tumor vol. growth in comparison with those animals in which part of the particles were found also in the liver and spleen. Therefore, our results point out several factors that should be considered to improve the treatment effectiveness of pancreatic cancer by magnetic hyperthermia.
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    Hyperthermia, the mild elevation of temp. to 40-43°C, can induce cancer cell death and enhance the effects of radiotherapy and chemotherapy. However, achievement of its full potential as a clin. relevant treatment modality has been restricted by its inability to effectively and preferentially heat malignant cells. The limited spatial resoln. may be circumvented by the i.v. administration of cancer-targeting magnetic nanoparticles that accumulate in the tumor, followed by the application of an alternating magnetic field to raise the temp. of the nanoparticles located in the tumor tissue. This targeted approach enables preferential heating of malignant cancer cells while sparing the surrounding normal tissue, potentially improving the effectiveness and safety of hyperthermia. Despite promising results in preclin. studies, there are numerous challenges that must be addressed before this technique can progress to the clinic. This review discusses these challenges and highlights the current understanding of targeted magnetic hyperthermia.
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    A review. Superparamagnetic iron oxide nanoparticles (SPIONs) have been extensively investigated during the last couple of decades because of their potential applications across various disciplines ranging from spintronics to nanotheranostics. However, pure iron oxide nanoparticles cannot meet the requirement for practical applications. Doping is considered as one of the most prominent and simplest techniques to achieve optimized multifunctional properties in nanomaterials. Doped iron oxides, particularly, rare-earth (RE) doped nanostructures have shown much-improved performance for a wide range of biomedical applications, including magnetic hyperthermia and magnetic resonance imaging (MRI), compared to pure iron oxide. Extensive investigations have revealed that bigger-sized RE ions possessing high magnetic moment and strong spin-orbit coupling can serve as promising dopants to significantly regulate the properties of iron oxides for advanced biomedical applications. This review provides a detailed investigation on the role of RE ions as primary dopants for engineering the structural and magnetic properties of Fe3O4 nanoparticles to carefully introspect and correlate their impact on cancer theranostics with a special focus on magnetic hyperthermia and MRI. In addn., prospects for achieving high-performance magnetic hyperthermia and MRI are thoroughly discussed. Finally, suggestions on future work in these two areas are also proposed.
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    Recent advances in magnetic fluid hyperthermia for cancer therapy
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    Recently, magnetic fluid hyperthermia using biocompatible magnetic nanoparticles as heat mediators for cancer therapy has been extensively investigated due to its high efficiency and limited side effects. However, the development of more efficient heat nanomediators that exhibit very high specific absorption rate (SAR) value is essential for clin. application to overcome the several restrictions previously encountered due to the large quantity of nanomaterial required for effective treatment. In this review, we focus on the current progress in the development of magnetic nanoparticles based hyperthermia therapy as well as combined therapy harnessing hyperthermia with heat-mediated drug delivery for cancer treatment. We also address the fundamental principles of magnetic hyperthermia, basics of magnetism including the effect of several parameters on heating capacity, synthetic methods and nanoparticle surface chem. needed to design and develop an ideal magnetic nanoparticle heat mediator suitable for clin. translation in cancer therapy.
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    Caro, C.; Egea-Benavente, D.; Polvillo, R.; Royo, J. L.; Pernia Leal, M.; García-Martín, M. L. Comprehensive Toxicity Assessment of PEGylated Magnetic Nanoparticles for in Vivo Applications. Colloids Surfaces B Biointerfaces 2019, 177, 253– 259,  DOI: 10.1016/j.colsurfb.2019.01.051
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    Comprehensive Toxicity Assessment of PEGylated Magnetic Nanoparticles for in vivo applications
    Caro, Carlos; Egea-Benavente, David; Polvillo, Rocio; Royo, Jose Luis; Pernia Leal, Manuel; Garcia-Martin, Maria Luisa
    Colloids and Surfaces, B: Biointerfaces (2019), 177 (), 253-259CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)
    Magnetic nanoparticles (MNPs) represent one of the greatest promises for the development of a new generation of diagnostic agents for magnetic resonance imaging, with improved specificity and safety. Indeed, during the last decade the no. of studies published in this field has grown exponentially. However, the clin. translation achieved so far has been very limited. This situation is likely related to the fact that most studies are focused on the in vitro characterization of these new nanomaterials, and very few provide an exhaustive in vivo characterization, where key aspects, such as pharmacokinetics, bioavailability, and, most importantly, toxicity, are properly evaluated. In this work, we propose a protocol for the comprehensive assessment of the toxicity of MNPs, based on the use of zebrafish embryos as an intermediate screening step between cell culture assays and studies in rodents. MNPs with different cores, ferrite and manganese ferrite oxide, and sizes between 3 and 20 nm, were evaluated. Cell viability at a concn. of 50μg/mL of PEGylated MNPs was above 90% in all cases. However, the exposure of zebrafish embryos to manganese based MNPs at concns. above 100μg/mL showed a low survival rate (<50%). In contrast, no mortality (survival rate ∼100%) and normal hatching rate were obtained for the iron oxide MNPs. Based on these results, together with the physicochem. and magnetic properties (r2 = 153.6 mM-1s-1), the PEGylated 20 nm cubic shape iron oxide MNPs were selected and tested in mice, showing very good MRI contrast and, as expected, absence of toxicity.
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    Malhotra, N.; Lee, J.-S.; Liman, R. A. D.; Ruallo, J. M. S.; Villaflores, O. B.; Ger, T.-R.; Hsiao, C.-D. Potential Toxicity of Iron Oxide Magnetic Nanoparticles: A Review. Molecules 2020, 25 (14), 3159,  DOI: 10.3390/molecules25143159
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    Potential toxicity of iron oxide magnetic nanoparticles: a review
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    Molecules (2020), 25 (14), 3159CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
    A review. The noteworthy intensification in the development of nanotechnol. has led to the development of various types of nanoparticles. The diverse applications of these nanoparticles make them desirable candidate for areas such as drug delivery, coasmetics, medicine, electronics, and contrast agents for magnetic resonance imaging (MRI) and so on. Iron oxide magnetic nanoparticles are a branch of nanoparticles which is specifically being considered as a contrast agent for MRI as well as targeted drug delivery vehicles, angiogenic therapy and chemotherapy as small size gives them advantage to travel intravascular or intracavity actively for drug delivery. Besides the mentioned advantages, the toxicity of the iron oxide magnetic nanoparticles is still less explored. For in vivo applications magnetic nanoparticles should be nontoxic and compatible with the body fluids. These particles tend to degrade in the body hence there is a need to understand the toxicity of the particles as whole and degraded products interacting within the body. Some nanoparticles have demonstrated toxic effects such inflammation, ulceration, and decreases in growth rate, decline in viability and triggering of neurobehavioral alterations in plants and cell lines as well as in animal models. The cause of nanoparticles' toxicity is attributed to their specific characteristics of great surface to vol. ratio, chem. compn., size, and dosage, retention in body, immunogenicity, organ specific toxicity, breakdown and elimination from the body. In the current review paper, we aim to sum up the current knowledge on the toxic effects of different magnetic nanoparticles on cell lines, marine organisms and rodents. We believe that the comprehensive data can provide significant study parameters and recent developments in the field. Thereafter, collecting profound knowledge on the background of the subject matter, will contribute to drive research in this field in a new sustainable direction.
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    Liu, X.; Zhang, Y.; Wang, Y.; Zhu, W.; Li, G.; Ma, X.; Zhang, Y.; Chen, S.; Tiwari, S.; Shi, K.; Zhang, S.; Fan, H. M.; Zhao, Y. X.; Liang, X. J. Comprehensive Understanding of Magnetic Hyperthermia for Improving Antitumor Therapeutic Efficacy. Theranostics 2020, 10 (8), 3793– 3815,  DOI: 10.7150/thno.40805
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    Comprehensive understanding of magnetic hyperthermia for improving antitumor therapeutic efficacy
    Liu, Xiaoli; Zhang, Yifan; Wang, Yanyun; Zhu, Wenjing; Li, Galong; Ma, Xiaowei; Zhang, Yihan; Chen, Shizhu; Tiwari, Shivani; Shi, Kejian; Zhang, Shouwen; Fan, Hai Ming; Zhao, Yong Xiang; Liang, Xing-Jie
    Theranostics (2020), 10 (8), 3793-3815CODEN: THERDS; ISSN:1838-7640. (Ivyspring International Publisher)
    A review. Magnetic hyperthermia (MH) has been introduced clin. as an alternative approach for the focal treatment of tumors. MH utilizes the heat generated by the magnetic nanoparticles (MNPs) when subjected to an alternating magnetic field (AMF). It has become an important topic in the nanomedical field due to their multitudes of advantages towards effective antitumor therapy such as high biosafety, deep tissue penetration, and targeted selective tumor killing. However, in order for MH to progress and to realize its paramount potential as an alternative choice for cancer treatment, tremendous challenges have to be overcome. Thus, the efficiency of MH therapy needs enhancement. In its recent 60-yr of history, the field of MH has focused primarily on heating using MNPs for therapeutic applications. Increasing the thermal conversion efficiency of MNPs is the fundamental strategy for improving therapeutic efficacy. Recently, emerging exptl. evidence indicates that MNPs-MH produces nano-scale heat effects without macroscopic temp. rise. A deep understanding of the effect of this localized induction heat for the destruction of subcellular/cellular structures further supports the efficacy of MH in improving therapeutic therapy. In this review, the currently available strategies for improving the antitumor therapeutic efficacy of MNPs-MH will be discussed. Firstly, the recent advancements in engineering MNP size, compn., shape, and surface to significantly improve their energy dissipation rates will be explored. Secondly, the latest studies depicting the effect of local induction heat for selectively disrupting cells/intracellular structures will be examd. Thirdly, strategies to enhance the therapeutics by combining MH therapy with chemotherapy, radiotherapy, immunotherapy, photothermal/photodynamic therapy (PDT), and gene therapy will be reviewed. Lastly, the prospect and significant challenges in MH-based antitumor therapy will be discussed. This review is to provide a comprehensive understanding of MH for improving antitumor therapeutic efficacy, which would be of utmost benefit towards guiding the users and for the future development of MNPs-MH towards successful application in medicine.
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    Erofeev, A.; Gorelkin, P.; Garanina, A.; Alova, A.; Efremova, M.; Vorobyeva, N.; Edwards, C.; Korchev, Y.; Majouga, A. Novel Method for Rapid Toxicity Screening of Magnetic Nanoparticles. Sci. Rep. 2018, 8 (1), 1– 11,  DOI: 10.1038/s41598-018-25852-4
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    Novel method for rapid toxicity screening of magnetic nanoparticles
    Erofeev, A.; Gorelkin, P.; Garanina, A.; Alova, A.; Efremova, M.; Vorobyeva, N.; Edwards, C.; Korchev, Y.; Majouga, A.
    Scientific Reports (2018), 8 (1), 1-11CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
    Iron oxide nanoparticles have attracted a great deal of research interest and have been widely used in bioscience and clin. research including as contrast agents for magnetic resonance imaging, hyperthermia and magnetic field assisted radionuclide therapy. It is therefore important to develop methods, which can provide high-throughput screening of biol. responses that can predict toxicity. The use of nanoelectrodes for single cell anal. can play a vital role in this process by providing relatively fast, comprehensive, and cost-effective assessment of cellular responses. We have developed a new method for in vitro study of the toxicity of magnetic nanoparticles (NP) based on the measurement of intracellular reactive oxygen species (ROS) by a novel nanoelectrode. Previous studies have suggested that ROS generation is frequently obsd. with NP toxicity. We have developed a stable probe for measuring intracellular ROS using platinized carbon nanoelectrodes with a cavity on the tip integrated into a micromanipulator on an upright microscope. Our results show a significant difference for intracellular levels of ROS measured in HEK293 and LNCaP cancer cells before and after exposure to 10 nm size iron oxide NP. These results are markedly different from ROS measured after cell incubation with the same concn. of NP using std. methods where no differences have been detected. In summary we have developed a label-free method for assessing nanoparticle toxicity using the rapid (less than 30 min) measurement of ROS with a novel nanoelectrode.
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    Setia, A.; Mehata, A. K.; Vikas; Malik, A. K.; Viswanadh, M. K.; Muthu, M. S. Theranostic Magnetic Nanoparticles: Synthesis, Properties, Toxicity, and Emerging Trends for Biomedical Applications. J. Drug Delivery Sci. Technol. 2023, 81, 104295,  DOI: 10.1016/j.jddst.2023.104295
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    Setia, Aseem; Mehata, Abhishesh Kumar; Vikas; Malik, Ankit Kumar; Viswanadh, Matte Kasi; Muthu, Madaswamy S.
    Journal of Drug Delivery Science and Technology (2023), 81 (), 104295CODEN: JDDSAL; ISSN:1773-2247. (Elsevier B.V.)
    A review. Nanotechnol. provides a wide range of nanosized devices, termed as nanotheranostics, that are integrated with diagnostic and therapeutic properties for real-time monitoring and treatment of diseases. In order to diagnose and cure diseases at the cellular and mol. level, the theranostic nanomedicine must first be able to circulate throughout the body without being destroyed by the host's immune system. Further, this can be linked to a biol. ligand for targeting a specific organ or tissue. Novel non-invasive diagnostic agents, such as magnetic nanoparticles (MNPs), are currently employed in magnetic resonance imaging (MRI). Previously, they have been used for imaging various diseases; but new developments have unlocked the way for targeting the drug to the cellular membrane and multi-modal imaging with MNPs. For the prodn. of MNPs, a wide range of synthetic methods such as phys. and thermal degrdn., hydrothermal prodn., microemulsion, co-pptn., and polyol processes have been used, which include few examples of biosynthetic techniques. One of the biggest concern with MNPs is that they have potential toxicity issues in biomedical applications. Due to their reactive surface features and their capacity to penetrate the cell and tissue membranes, MNPs can elicit a powerful cytotoxic effect and hyperthermia. Numerous labs. have studied in vitro cellular toxicity of MNPs in a wide variety of cancer and normal cell lines, and their findings established the fact that at low concns., MNPs are nontoxic, and at high concns., they have marginal toxicity, demonstrating their biocompatibility and acceptable safety profile. Diagnostic imaging using nanosystems can be performed using the aforementioned approaches, including MRI, optical imaging, nuclear imaging, computed tomog., ultrasound etc. In this article, various theranostic magnetic nanosystems are discussed in the context of their manufg. and development for therapeutic and diagnostic use, focusing mainly on in vitro and in vivo applications. Further emphasis on their potential for integrating other nanostructures with current biotechnol., as well as the special qualities of magnetic nanosystems are further highlighted to explain the future role of magnetic nanosystems in the successful therapy.
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  15. 15
    Liu, X.; Zhang, Y.; Wang, Y.; Zhu, W.; Li, G.; Ma, X.; Zhang, Y.; Chen, S.; Tiwari, S.; Shi, K.; Zhang, S.; Fan, H. M.; Zhao, Y. X.; Liang, X. J. Comprehensive Understanding of Magnetic Hyperthermia for Improving Antitumor Therapeutic Efficacy. Theranostics 2020, 10 (8), 3793– 3815,  DOI: 10.7150/thno.40805
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    15
    Comprehensive understanding of magnetic hyperthermia for improving antitumor therapeutic efficacy
    Liu, Xiaoli; Zhang, Yifan; Wang, Yanyun; Zhu, Wenjing; Li, Galong; Ma, Xiaowei; Zhang, Yihan; Chen, Shizhu; Tiwari, Shivani; Shi, Kejian; Zhang, Shouwen; Fan, Hai Ming; Zhao, Yong Xiang; Liang, Xing-Jie
    Theranostics (2020), 10 (8), 3793-3815CODEN: THERDS; ISSN:1838-7640. (Ivyspring International Publisher)
    A review. Magnetic hyperthermia (MH) has been introduced clin. as an alternative approach for the focal treatment of tumors. MH utilizes the heat generated by the magnetic nanoparticles (MNPs) when subjected to an alternating magnetic field (AMF). It has become an important topic in the nanomedical field due to their multitudes of advantages towards effective antitumor therapy such as high biosafety, deep tissue penetration, and targeted selective tumor killing. However, in order for MH to progress and to realize its paramount potential as an alternative choice for cancer treatment, tremendous challenges have to be overcome. Thus, the efficiency of MH therapy needs enhancement. In its recent 60-yr of history, the field of MH has focused primarily on heating using MNPs for therapeutic applications. Increasing the thermal conversion efficiency of MNPs is the fundamental strategy for improving therapeutic efficacy. Recently, emerging exptl. evidence indicates that MNPs-MH produces nano-scale heat effects without macroscopic temp. rise. A deep understanding of the effect of this localized induction heat for the destruction of subcellular/cellular structures further supports the efficacy of MH in improving therapeutic therapy. In this review, the currently available strategies for improving the antitumor therapeutic efficacy of MNPs-MH will be discussed. Firstly, the recent advancements in engineering MNP size, compn., shape, and surface to significantly improve their energy dissipation rates will be explored. Secondly, the latest studies depicting the effect of local induction heat for selectively disrupting cells/intracellular structures will be examd. Thirdly, strategies to enhance the therapeutics by combining MH therapy with chemotherapy, radiotherapy, immunotherapy, photothermal/photodynamic therapy (PDT), and gene therapy will be reviewed. Lastly, the prospect and significant challenges in MH-based antitumor therapy will be discussed. This review is to provide a comprehensive understanding of MH for improving antitumor therapeutic efficacy, which would be of utmost benefit towards guiding the users and for the future development of MNPs-MH towards successful application in medicine.
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  16. 16
    Walter, A.; Billotey, C.; Garofalo, A.; Ulhaq-Bouillet, C.; Lefevre, C.; Taleb, J.; Laurent, S.; Vander Elst, L.; Muller, R. N.; Lartigue, L.; Gazeau, F.; Felder-Flesch, D.; Begin-Colin, S. Mastering the Shape and Composition of Dendronized Iron Oxide Nanoparticles to Tailor Magnetic Resonance Imaging and Hyperthermia. Chem. Mater. 2014, 26 (18), 5252– 5264,  DOI: 10.1021/cm5019025
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    16
    Mastering the Shape and Composition of Dendronized Iron Oxide Nanoparticles To Tailor Magnetic Resonance Imaging and Hyperthermia
    Walter, Aurelie; Billotey, Claire; Garofalo, Antonio; Ulhaq-Bouillet, Corinne; Lefevre, Christophe; Taleb, Jacqueline; Laurent, Sophie; Vander Elst, Luce; Muller, Robert N.; Lartigue, Lenaic; Gazeau, Florence; Felder-Flesch, Delphine; Begin-Colin, Sylvie
    Chemistry of Materials (2014), 26 (18), 5252-5264CODEN: CMATEX; ISSN:0897-4756. (American Chemical Society)
    The current challenge in the field of nanomedicine is the design of multifunctional nano-objects effective both for the diagnosis and treatment of diseases. Dendronized FeO1-x@Fe3-xO4 nanoparticles with spherical, cubic, and octopode shapes and oxidized Fe3-xO4 nanocubes were synthesized and structurally and magnetically characterized. Strong exchange bias properties are highlighted in core-shell nanoparticles (NPs) due to magnetic interactions between their antiferromagnetic core and ferrimagnetic shell. Both in vitro relaxivity measurements and NMR distribution profiles confirmed the very good in vitro magnetic resonance imaging (MRI) properties of core-shell and cubic shape NPs, esp. at low concn. This might be related to the supplementary anisotropy introduced by the exchange bias properties and the cubic shape. The high heating values of core-shell NPs and oxidized nanocubes at low concn. are attributed to dipolar interactions inducing different clustering states, as a function of concn. In vivo MRI studies have also evidenced a clustering effect at the injection point, depending on the concn., and confirmed the very good in vivo MRI properties of core-shell NPs and oxidized nanocubes in particular at low concn. These core-shell and cubic shape dendronized nano-objects are very suitable to combine MRI and hyperthermia properties at low injected doses.
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  17. 17
    Gavilán, H.; Simeonidis, K.; Myrovali, E.; Mazarío, E.; Chubykalo-Fesenko, O.; Chantrell, R.; Balcells, L.; Angelakeris, M.; Morales, M. P.; Serantes, D. How Size, Shape and Assembly of Magnetic Nanoparticles Give Rise to Different Hyperthermia Scenarios. Nanoscale 2021, 13 (37), 15631– 15646,  DOI: 10.1039/D1NR03484G
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    17
    How size, shape and assembly of magnetic nanoparticles give rise to different hyperthermia scenarios
    Gavilan, H.; Simeonidis, K.; Myrovali, E.; Mazario, E.; Chubykalo-Fesenko, O.; Chantrell, R.; Balcells, Ll.; Angelakeris, M.; Morales, M. P.; Serantes, D.
    Nanoscale (2021), 13 (37), 15631-15646CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
    The use of magnetic nanoparticles (MNPs) to locally increase the temp. at the nanoscale under the remote application of alternating magnetic fields (magnetic particle hyperthermia, MHT) has become an important subject of nanomedicine multidisciplinary research, focusing among other topics on the optimization of the heating performance of MNPs and their assemblies under the effect of the magnetic field. We report exptl. data of heat released by MNPs using a wide range of anisometric shapes and their assemblies in different media. We outline a basic theor. investigation, which assists the interpretation of the exptl. data, including the effect of the size, shape and assembly of MNPs on the MNPs' hysteresis loops and the max. heat delivered. We report heat release data of anisometric MNPs, including nanodisks, spindles (elongated nanoparticles) and nanocubes, analyzing, for a given shape, the size dependence. We study the MNPs either acting as individuals or assembled through a magnetic-field-assisted method. Thus, the phys. geometrical arrangement of these anisometric particles, the magnetization switching and the heat release (by means of the detn. of the specific adsorption rate, SAR values) under the application of AC fields have been analyzed and compared in aq. suspensions and after immobilization in agar matrix mimicking the tumor environment. The different nano-systems were analyzed when dispersed at random or in assembled configurations. We report a systematic fall in the SAR for all anisometric MNPs randomly embedded in a viscous environment. However, certain anisometric shapes will have a less marked, an almost total preservation or even an increase in SAR when embedded in a viscous environment with certain orientation, in contrast to the measurements in water soln. Discrepancies between theor. and exptl. values reflect the complexity of the systems due to the interplay of different factors such as size, shape and nanoparticle assembly due to magnetic interactions. We demonstrate that magnetic assembly holds great potential for producing materials with high functional and structural diversity, as we transform our nanoscale building blocks (anisometric MNPs) into a material displaying enhanced SAR properties.
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  18. 18
    Lee, J.-H.; Jang, J.; Choi, J.; Moon, S. H.; Noh, S.; Kim, J.; Kim, J.-G.; Kim, I.-S.; Park, K. I.; Cheon, J. Exchange-Coupled Magnetic Nanoparticles for Efficient Heat Induction. Nat. Nanotechnol. 2011, 6 (7), 418– 422,  DOI: 10.1038/nnano.2011.95
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    18
    Exchange-coupled magnetic nanoparticles for efficient heat induction
    Lee, Jae-Hyun; Jang, Jung-tak; Choi, Jin-sil; Moon, Seung Ho; Noh, Seung-hyun; Kim, Ji-wook; Kim, Jin-Gyu; Kim, Il-Sun; Park, Kook In; Cheon, Jinwoo
    Nature Nanotechnology (2011), 6 (7), 418-422CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)
    The conversion of electromagnetic energy into heat by nanoparticles has the potential to be a powerful, non-invasive technique for biotechnol. applications such as drug release, disease treatment and remote control of single cell functions, but poor conversion efficiencies have hindered practical applications so far. In this Letter, we demonstrate a significant increase in the efficiency of magnetic thermal induction by nanoparticles. We take advantage of the exchange coupling between a magnetically hard core and magnetically soft shell to tune the magnetic properties of the nanoparticle and maximize the specific loss power, which is a gauge of the conversion efficiency. The optimized core-shell magnetic nanoparticles have specific loss power values that are an order of magnitude larger than conventional iron-oxide nanoparticles. We also perform an antitumor study in mice, and find that the therapeutic efficacy of these nanoparticles is superior to that of a common anticancer drug.
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  19. 19
    Jun, Y. W.; Seo, J. W.; Cheon, J. Nanoscaling Laws of Magnetic Nanoparticles and Their Applicabilities in Biomedical Sciences. Acc. Chem. Res. 2008, 41 (2), 179– 189,  DOI: 10.1021/ar700121f
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    19
    Nanoscaling Laws of Magnetic Nanoparticles and Their Applicabilities in Biomedical Sciences
    Jun, Young-wook; Seo, Jung-wook; Cheon, Jinwoo
    Accounts of Chemical Research (2008), 41 (2), 179-189CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
    A review. Magnetic nanoparticles, which exhibit a variety of unique magnetic phenomena that are drastically different from those of their bulk counterparts, are garnering significant interest since these properties can be advantageous for utilization in a variety of applications ranging from storage media for magnetic memory devices to probes and vectors in the biomedical sciences. In this Account, the authors discuss the nanoscaling laws of magnetic nanoparticles including metals, metal ferrites, and metal alloys, while focusing on their size, shape, and compn. effects. Their fundamental magnetic properties such as blocking temp. (Tb), spin life time (τ), coercivity (Hc), and susceptibility (χ) are strongly influenced by the nanoscaling laws, and as a result, these scaling relationships can be leveraged to control magnetism from the ferromagnetic to the superparamagnetic regimes. At the same time, they can be used to tune magnetic values including Hc, χ, and remanence (Mr). For example, life time of magnetic spin is directly related to the magnetic anisotropy energy (KuV) and also the size and vol. of nanoparticles. The blocking temp. (Tb) changes from room temp. to 10 K as the size of cobalt nanoparticles is reduced from 13 to 2 nm. Similarly, Hc is highly susceptible to the anisotropy of nanoparticles, while satn. magnetization is directly related to the canting effects of the disordered surface magnetic spins and follows a linear relation upon plotting of ms1/3 vs. r-1. Therefore, the nanoscaling laws of magnetic nanoparticles are important not only for understanding the behavior of existing materials but also for developing novel nanomaterials with superior properties. Since magnetic nanoparticles can be easily conjugated with biol. important constituents such as DNA, peptides, and antibodies, it is possible to construct versatile nano-bio hybrid particles, which simultaneously possess magnetic and biol. functions for biomedical diagnostics and therapeutics. As demonstrated in this Account, nanoscaling laws for magnetic components are crit. to the design of optimized magnetic characteristics of hybrid nanoparticles and their enhanced applicability in the biomedical sciences including their utilizations as contrast enhancement agents for magnetic resonance imaging (MRI), ferromagnetic components for nano-bio hybrid structures, and translational vectors for magnetophoretic sensing of biol. species. In particular, systematic modulation of satn. magnetization of nanoparticle probes is important to maximize MR contrast effects and magnetic sepn. of biol. targets.
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  20. 20
    Mai, B. T.; Balakrishnan, P. B.; Barthel, M. J.; Piccardi, F.; Niculaes, D.; Marinaro, F.; Fernandes, S.; Curcio, A.; Kakwere, H.; Autret, G.; Cingolani, R.; Gazeau, F.; Pellegrino, T. Thermoresponsive Iron Oxide Nanocubes for an Effective Clinical Translation of Magnetic Hyperthermia and Heat-Mediated Chemotherapy. ACS Appl. Mater. Interfaces 2019, 11 (6), 5727– 5739,  DOI: 10.1021/acsami.8b16226
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    20
    Thermoresponsive Iron Oxide Nanocubes for an Effective Clinical Translation of Magnetic Hyperthermia and Heat-Mediated Chemotherapy
    Mai Binh T; Balakrishnan Preethi B; Barthel Markus J; Piccardi Federica; Niculaes Dina; Marinaro Federica; Fernandes Soraia; Curcio Alberto; Kakwere Hamilton; Cingolani Roberto; Pellegrino Teresa; Mai Binh T; Balakrishnan Preethi B; Niculaes Dina; Autret Gwennhael; Gazeau Florence
    ACS applied materials & interfaces (2019), 11 (6), 5727-5739 ISSN:.
    The use of magnetic nanoparticles in oncothermia has been investigated for decades, but an effective combination of magnetic nanoparticles and localized chemotherapy under clinical magnetic hyperthermia (MH) conditions calls for novel platforms. In this study, we have engineered magnetic thermoresponsive iron oxide nanocubes (TR-cubes) to merge MH treatment with heat-mediated drug delivery, having in mind the clinical translation of the nanoplatform. We have chosen iron oxide based nanoparticles with a cubic shape because of their outstanding heat performance under MH clinical conditions, which makes them benchmark agents for MH. Accomplishing a surface-initiated polymerization of strongly interactive nanoparticles such as our iron oxide nanocubes, however, remains the main challenge to overcome. Here, we demonstrate that it is possible to accelerate the growth of a polymer shell on each nanocube by simple irradiation of a copper-mediated polymerization with a ultraviolet light (UV) light, which both speeds up the polymerization and prevents nanocube aggregation. Moreover, we demonstrate herein that these TR-cubes can carry chemotherapeutic doxorubicin (DOXO-loaded-TR-cubes) without compromising their thermoresponsiveness both in vitro and in vivo. In vivo efficacy studies showed complete tumor suppression and the highest survival rate for animals that had been treated with DOXO-loaded-TR-cubes, only when they were exposed to MH. The biodistribution of intravenously injected TR-cubes showed signs of renal clearance within 1 week and complete clearance after 5 months. This biomedical platform works under clinical MH conditions and at a low iron dosage, which will enable the translation of dual MH/heat-mediated chemotherapy, thus overcoming the clinical limitation of MH: i.e., being able to monitor tumor progression post-MH-treatment by magnetic resonance imaging (MRI).
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  21. 21
    Hammad, M.; Nica, V.; Hempelmann, R. Synthesis and Characterization of Bi-Magnetic Core/Shell Nanoparticles for Hyperthermia Applications. IEEE Trans. Magn. 2017, 53 (4), 1,  DOI: 10.1109/TMAG.2016.2635696
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  22. 22
    Hammad, M.; Nica, V.; Hempelmann, R. On-Off Switch-Controlled Doxorubicin Release from Thermo- and PH-Responsive Coated Bimagnetic Nanocarriers. J.Nanopart. Res. 2016, 18 (8), 234,  DOI: 10.1007/s11051-016-3550-7
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    There is no corresponding record for this reference.
  23. 23
    Hammad, M.; Nica, V.; Hempelmann, R. On-Command Controlled Drug Release by Diels-Alder Reaction Using Bi-Magnetic Core/Shell Nano-Carriers. Colloids Surfaces B Biointerfaces 2017, 150, 15– 22,  DOI: 10.1016/j.colsurfb.2016.11.005
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    23
    On-command controlled drug release by Diels-Alder reaction using Bi-magnetic core/shell nano-carriers
    Hammad, Mohaned; Nica, Valentin; Hempelmann, Rolf
    Colloids and Surfaces, B: Biointerfaces (2017), 150 (), 15-22CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)
    A novel bi-functional thermo-responsive system, consisting of core/shell bi-magnetic nanoparticles with furan surface functionality, is bonded with N-(2-Carboxyethyl)maleimide through Diels-Alder reaction. The chemotherapeutics doxorubicin is attached onto the surface, with a high loading efficiency of 92%. This system with high responsiveness to a high frequency external alternating magnetic field shows a very good therapeutic efficiency in hyperthermia and drug release at relatively low temps. (50°C). Polyhedron-shaped bi-magnetic nanoparticles ([email protected]) exhibit a significant increase of the specific energy absorption rate up to 455 W/g compared with the core nanoparticles (200 W/g). Real-time florescence spectroscopy studies demonstrate rapid release of doxorubicin up to 50% in 5 min and up to 92% after 15 min upon exposure to high frequency external alternating magnetic field. The stability is evaluated for 8 wk in phosphate buffer saline with a doxorubicin payload of 85%. In vitro studies using std. MTT cell assays with HeLa and Hep G2 lines prove an excellent biocompatibility with about 90% of cell viability after 24 h of treatment within the highest concn. of functionalized magnetic nanoparticles (200μg/mL). The results indicate a controlled drug release mediated by thermo-responsive switching under applied alternating magnetic field.
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  24. 24
    Tapeinos, C.; Marino, A.; Battaglini, M.; Migliorin, S.; Brescia, R.; Scarpellini, A.; De Julián Fernández, C.; Prato, M.; Drago, F.; Ciofani, G. Stimuli-Responsive Lipid-Based Magnetic Nanovectors Increase Apoptosis in Glioblastoma Cells through Synergic Intracellular Hyperthermia and Chemotherapy. Nanoscale 2019, 11 (1), 72– 88,  DOI: 10.1039/C8NR05520C
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    24
    Stimuli-responsive lipid-based magnetic nanovectors increase apoptosis in glioblastoma cells through synergic intracellular hyperthermia and chemotherapy
    Tapeinos, Christos; Marino, Attilio; Battaglini, Matteo; Migliorin, Simone; Brescia, Rosaria; Scarpellini, Alice; De Julian Fernandez, Cesar; Prato, Mirko; Drago, Filippo; Ciofani, Gianni
    Nanoscale (2019), 11 (1), 72-88CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
    In this study, taking into consideration the limitations of current treatments of glioblastoma multiforme, we fabricated a biomimetic lipid-based magnetic nanovector with a good loading capacity and a sustained release profile of the encapsulated chemotherapeutic drug, temozolomide. In addn., these nanovectors presented excellent specific absorption rate values (up to 1345 W g-1) considering the size of the magnetic component, rendering them suitable as potential hyperthermia agents. The presented nanovectors were progressively internalized in U-87 MG cells and in their acidic compartments (i.e., lysosomes and late endosomes) without affecting the viability of the cells, and their ability to cross the blood-brain barrier was preliminarily investigated using an in vitro brain endothelial cell-model. When stimulated with alternating magnetic fields (20 mT, 750 kHz), the nanovectors demonstrated their ability to induce mild hyperthermia (43°C) and strong anticancer effects against U-87 MG cells (scarce survival of cells characterized by low proliferation rates and high apoptosis levels). The optimal anticancer effects resulted from the synergic combination of hyperthermia chronic stimulation and the controlled temozolomide release, highlighting the potential of the proposed drug-loaded lipid magnetic nanovectors for treatment of glioblastoma multiforme.
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  25. 25
    Gavrilov-Isaac, V.; Neveu, S.; Dupuis, V.; Taverna, D.; Gloter, A.; Cabuil, V. Synthesis of Trimagnetic Multishell MnFe2O4@CoFe2O4@NiFe2O4 Nanoparticles. Small 2015, 11 (22), 2614– 2618,  DOI: 10.1002/smll.201402845
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    25
    Synthesis of Trimagnetic Multishell MnFe2O4@CoFe2O4@NiFe2O4 Nanoparticles
    Gavrilov-Isaac, Veronica; Neveu, Sophie; Dupuis, Vincent; Taverna, Dario; Gloter, Alexandre; Cabuil, Valerie
    Small (2015), 11 (22), 2614-2618CODEN: SMALBC; ISSN:1613-6810. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The authors report the synthesis and characterization of trimagnetic multishell MnFe2O4@CoFe2O4@NiFe2O4 nanoparticles with ferrite. These particles are a combination of a hard phase (CoFe2O4) and two soft phases (MnFe2O4 and NiFe2O4) and have unique magnetic characteristics. To synthesize MnFe2O4@CoFe2O4 core@shell and MnFe2O4@CoFe2O4@NiFe2O4 core@shell@shell nanoparticles, a seed-mediated growth at high temp. was used. The process and magnetic properties are described. The model is a good indication to predict the qual. modification of the coercive field when a new shell is added, but it needs to be improved in order to give quant. correct predictions. In particular, the quality of the interfaces between the different materials of the core and shells certainly plays an important role.
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  26. 26
    Nuñez, J. M.; Hettler, S.; Lima, E.; Goya, G. F.; Arenal, R.; Zysler, R. D.; Aguirre, M. H.; Winkler, E. L. Onion-like Fe3O4/MgO/CoFe2O4Magnetic Nanoparticles: New Ways to Control Magnetic Coupling between Soft and Hard Magnetic Phases. J. Mater. Chem. C 2022, 10 (41), 15339– 15352,  DOI: 10.1039/D2TC03144B
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    26
    Onion-like Fe3O4/MgO/CoFe2O4 magnetic nanoparticles: new ways to control magnetic coupling between soft and hard magnetic phases
    Nunez, Jorge M.; Hettler, Simon; Lima Jr, Enio; Goya, Gerardo F.; Arenal, Raul; Zysler, Roberto D.; Aguirre, Myriam H.; Winkler, Elin L.
    Journal of Materials Chemistry C: Materials for Optical and Electronic Devices (2022), 10 (41), 15339-15352CODEN: JMCCCX; ISSN:2050-7534. (Royal Society of Chemistry)
    The control of magnetization inversion dynamics is one of the main challenges driving the design of new nanostructured magnetic materials for magnetoelectronic applications. Nanoparticles with an onion-like architecture offer a unique opportunity to expand the possibilities of combining different phases at the nanoscale and also modulating the coupling between magnetic phases by introducing spacers into the same structure. Here, we report the fabrication, by a three-step high temp. decompn. method, of Fe3O4/MgO/CoFe2O4 onion-like nanoparticles and their detailed structural anal., elemental compositional maps and magnetic response. The core/shell/shell nanoparticles present epitaxial growth and cubic shape with an overall size of (29 ± 6) nm. These nanoparticles consist of a cubic iron oxide core of 22 ± 4nm in size covered by two shells, the inner of magnesium oxide and the outer of cobalt ferrite of thicknesses 1 and 2.5 nm, resp. The magnetization measurements show a single reversion magnetization curve and the enhancement of the coercivity field, from HC 608 Oe for the Fe3O4/MgO to HC 5890 Oe for the Fe3O4/MgO/CoFe2O4 nanoparticles at T = 5 K, ascribed to the coupling between both ferrimagnetic phases with a coupling const. of JC= 2 erg cm-2. The system also exhibits an exchange bias effect, where the exchange bias field increases up to HEB 2850 Oe at 5 K accompanied by the broadening of the magnetization loop of HC 6650 Oe. This exchange bias effect originates from the freezing of the surface spins below the freezing temp. HF= 32 K that pinned the magnetic moment of the cobalt ferrite shell.
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  27. 27
    Grauer, O.; Jaber, M.; Hess, K.; Weckesser, M.; Schwindt, W.; Maring, S.; Wölfer, J.; Stummer, W. Combined Intracavitary Thermotherapy with Iron Oxide Nanoparticles and Radiotherapy as Local Treatment Modality in Recurrent Glioblastoma Patients. J. Neurooncol. 2019, 141 (1), 83– 94,  DOI: 10.1007/s11060-018-03005-x
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    27
    Combined intracavitary thermotherapy with iron oxide nanoparticles and radiotherapy as local treatment modality in recurrent glioblastoma patients
    Grauer Oliver; Jaber Mohammed; Wolfer Johannes; Stummer Walter; Hess Katharina; Weckesser Matthias; Schwindt Wolfram; Maring Stephan; Wolfer Johannes
    Journal of neuro-oncology (2019), 141 (1), 83-94 ISSN:.
    BACKGROUND: There is an increasing interest in local tumor ablative treatment modalities that induce immunogenic cell death and the generation of antitumor immune responses. METHODS: We report six recurrent glioblastoma patients who were treated with intracavitary thermotherapy after coating the resection cavity wall with superparamagnetic iron oxide nanoparticles ("NanoPaste" technique). Patients underwent six 1-h hyperthermia sessions in an alternating magnetic field and, if possible, received concurrent fractionated radiotherapy at a dose of 39.6 Gy. RESULTS: There were no major side effects during active treatment. However, after 2-5 months, patients developed increasing clinical symptoms. CT scans showed tumor flare reactions with prominent edema around nanoparticle deposits. Patients were treated with dexamethasone and, if necessary, underwent re-surgery to remove nanoparticles. Histopathology revealed sustained necrosis directly adjacent to aggregated nanoparticles without evidence for tumor activity. Immunohistochemistry showed upregulation of Caspase-3 and heat shock protein 70, prominent infiltration of macrophages with ingested nanoparticles and CD3(+) T-cells. Flow cytometric analysis of freshly prepared tumor cell suspensions revealed increased intracellular ratios of IFN-γ to IL-4 in CD4(+) and CD8(+) memory T cells, and activation of tumor-associated myeloid cells and microglia with upregulation of HLA-DR and PD-L1. Two patients had long-lasting treatment responses > 23 months without receiving any further therapy. CONCLUSION: Intracavitary thermotherapy combined with radiotherapy can induce a prominent inflammatory reaction around the resection cavity which might trigger potent antitumor immune responses possibly leading to long-term stabilization of recurrent GBM patients. These results warrant further investigations in a prospective phase-I trial.
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  28. 28
    Park, Y.; Demessie, A. A.; Luo, A.; Taratula, O. R.; Moses, A. S.; Do, P.; Campos, L.; Jahangiri, Y.; Wyatt, C. R.; Albarqi, H. A.; Farsad, K.; Slayden, O. D.; Taratula, O. Targeted Nanoparticles with High Heating Efficiency for the Treatment of Endometriosis with Systemically Delivered Magnetic Hyperthermia. Small 2022, 18 (24), 1– 15,  DOI: 10.1002/smll.202107808
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    Guntnur, R. T.; Muzzio, N.; Gomez, A.; Macias, S.; Galindo, A.; Ponce, A.; Romero, G. On-Demand Chemomagnetic Modulation of Striatal Neurons Facilitated by Hybrid Magnetic Nanoparticles. Adv. Funct. Mater. 2022, 32, 2204732,  DOI: 10.1002/adfm.202204732
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    29
    On-Demand Chemomagnetic Modulation of Striatal Neurons Facilitated by Hybrid Magnetic Nanoparticles
    Guntnur, Rohini Thevi; Muzzio, Nicolas; Gomez, Amanda; Macias, Sean; Galindo, Arturo; Ponce, Arturo; Romero, Gabriela
    Advanced Functional Materials (2022), 32 (35), 2204732CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Minimally invasive manipulation of cell signaling is crit. in basic neuroscience research and in developing therapies for neurol. disorders. Here, a wireless chemomagnetic neuromodulation platform for the on-demand control of primary striatal neurons that relies on nanoscale heating events is described. Iron oxide magnetic nanoparticles (MNPs) are functionally coated with thermoresponsive poly (oligo (ethylene glycol) Me ether methacrylate) (POEGMA) brushes loaded with dopamine. Dopamine loaded MNPs-POEGMA are co-cultured with primary striatal neurons. When alternating magnetic fields (AMF) are applied, MNPs undergo hysteresis power loss and dissipate heat. The local heat produced by MNPs initiates a thermodn. phase transition on POEGMA brushes resulting in polymer collapse and dopamine release. AMF-triggered dopamine release enhances the response of dopamine ion channels expressed on the cell membranes enhancing the activity ≈50% of striatal neurons subjected to the treatment. Chemomagnetic actuation on dopamine receptors is confirmed by blocking D1 and D2 receptors. The reversible thermodn. phase transition of POEGMA brushes allow the on-demand release of dopamine in multiple microdoses. AMF-triggered dopamine release from MNPs-POEGMA causes neither cell cytotoxicity nor promotes cell reactive oxygen species prodn. This research represents a fundamental step forward for the chemomagnetic control of neural activity using hybrid magnetic nanomaterials with tailored phys. properties.
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  30. 30
    Pucci, C.; Degl’Innocenti, A.; Belenli Gümüş, M.; Ciofani, G. Superparamagnetic Iron Oxide Nanoparticles for Magnetic Hyperthermia: Recent Advancements, Molecular Effects, and Future Directions in the Omics Era. Biomater. Sci. 2022, 10 (9), 2103– 2121,  DOI: 10.1039/D1BM01963E
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    30
    Superparamagnetic iron oxide nanoparticles for magnetic hyperthermia: recent advancements, molecular effects, and future directions in the omics era
    Pucci, Carlotta; Degl'Innocenti, Andrea; Belenli Gumus, Melike; Ciofani, Gianni
    Biomaterials Science (2022), 10 (9), 2103-2121CODEN: BSICCH; ISSN:2047-4849. (Royal Society of Chemistry)
    A review. Superparamagnetic iron oxide nanoparticles (SPIONs) have attracted attention in the biomedical field thanks to their ability to prompt hyperthermia in response to an alternated magnetic field. Hyperthermia is well known for inducing cell death, in particular in tumor cells, which seem to have a higher sensitivity to temp. increases. For this reason, hyperthermia has been recommended as a therapeutic tool against cancer. Despite the potentialities of this approach, little is still known about the effects provoked by magnetic hyperthermia at the mol. level, and about the particular cell death mechanisms that are activated. Nevertheless, in-depth knowledge of this aspect would allow improvement of therapeutic outcomes and favor clin. translation. Moreover, in the last few decades, a lot of effort has been put into finding an effective delivery strategy that could improve SPION biodistribution and localisation at the action site. The aim of this review is to provide a general outline of magnetic hyperthermia, focusing on iron oxide nanoparticles and their interactions with magnetic fields, as well as on new strategies to efficiently deliver them to the target site, and on recent in vitro and in vivo studies proposing possible cell death pathways activated by the treatment. We will also cover their current clin. status, and discuss the contributions of omics in understanding mol. interactions between iron oxide nanoparticles and the biol. environment.
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    Pudlarz, A.; Szemraj, J. Nanoparticles as Carriers of Proteins, Peptides and Other Therapeutic Molecules. Open Life Sci. 2018, 13 (1), 285– 298,  DOI: 10.1515/biol-2018-0035
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    31
    Nanoparticles as carriers of proteins, peptides and other therapeutic molecules
    Pudlarz, Agnieszka; Szemraj, Janusz
    Open Life Sciences (2018), 13 (1), 285-298CODEN: OLSPBT; ISSN:2391-5412. (De Gruyter Open Ltd.)
    Nanoparticles have many applications both in industry and medicine. Depending upon their phys. and chem. properties, they can be used as carriers of therapeutic mols. or as therapeutics. Nanoparticles are made of synthetic or natural polymers, lipids or metals. Their use allows for faster transport to the place of action, thus prolonging its presence in the body and limiting side effects. In addn., the use of such a drug delivery system protects the drug from rapid disintegration and elimination from the body. In recent years, the use of proteins and peptides as therapeutic mols. has grown significantly. Unfortunately, proteins are subject to enzymic digestion and can cause unwanted immune response beyond therapeutic action. The use of drug carriers can minimize undesirable side effects and reduce the dose of medication needed to achieve the therapeutic effect. The current study presents the use of several selected drug delivery systems for the delivery of proteins, peptides and other therapeutic mols.
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    Longoria-García, S.; Sánchez-Domínguez, C. N.; Gallardo-Blanco, H. Recent Applications of Cell-Penetrating Peptide Guidance of Nanosystems in Breast and Prostate Cancer (Review). Oncol. Lett. 2022, 23 (3), 103,  DOI: 10.3892/ol.2022.13223
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    32
    Recent applications of cell-penetrating peptide guidance of nanosystems in breast and prostate cancer (review)
    Longoria-Garcia, Samuel; Sanchez-Dominguez, Celia Nohemi; Gallardo-Blanco, Hugo Leonid
    Oncology Letters (2022), 23 (3), 103CODEN: OLNEB5; ISSN:1792-1082. (Spandidos Publications Ltd.)
    Cell-penetrating peptides (CPPs) are small peptides from natural sources or designed from other protein sequences that can penetrate cell membranes. This property has been used in biomedicine to add them to biomols. to improve their capacity for cell internalization and as a guidance tool for specific cell types. CPPs have been shown to enhance cellular uptake in vitro and in vivo, improving the efficacy of anticancer drugs such as doxorubicin and paclitaxel, while also limiting their cytotoxic effects on healthy cells and tissues. The current study reviews the internalization and major therapeutic results achieved from the functionalization of nanosystems with CPPs for guidance into breast and prostate cancer cells in vitro and in vivo. In addn., the practical results obtained are specifically discussed for use as a starting point for scientists looking to begin research in this field.
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    Zhu, L.; Zhong, Y.; Wu, S.; Yan, M.; Cao, Y.; Mou, N.; Wang, G.; Sun, D.; Wu, W. Cell Membrane Camouflaged Biomimetic Nanoparticles: Focusing on Tumor Theranostics. Mater. Today Bio 2022, 14, 100228,  DOI: 10.1016/j.mtbio.2022.100228
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    Cell membrane camouflaged biomimetic nanoparticles: Focusing on tumor theranostics
    Zhu, Li; Zhong, Yuan; Wu, Shuai; Yan, Meng; Cao, Yu; Mou, Nianlian; Wang, Guixue; Sun, Da; Wu, Wei
    Materials Today Bio (2022), 14 (), 100228CODEN: MTBAC2; ISSN:2590-0064. (Elsevier Ltd.)
    Nanoparticles (NPs) modified by cell membranes represent an emerging biomimetic platform that can mimic the innate biol. functions resulting from the various cell membranes in biol. systems. researchers focus on constructing the cell membrane camouflaged NPs using a wide variety of cells, such as red blood cell membranes (RBC), macrophages and cancer cells. Cell membrane camouflaged NPs (CMNPs) inherit the compn. of cell membranes, including specific receptors, antigens, proteins, for target delivering to the tumor, escaping immune from clearance, and prolonging the blood circulation time, etc. Combining cell membrane-derived biol. functions and the NP cores acted cargo carriers to encapsulate the imaging agents, CMNPs are widely developed to apply in tumor imaging techniques, including computed tomog. (CT), magnetic resonance imaging (MRI), fluorescence imaging (FL) and photoacoustic imaging (PA). Herein, in this review, we systematically summarize the superior functions of various CMNPs in tumor imaging, esp. highlighting the advanced applications in different imaging techniques, which is to provide the theor. supports for the development of precise guided imaging and tumor treatment.
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    Rao, L.; Cai, B.; Bu, L. L.; Liao, Q. Q.; Guo, S. S.; Zhao, X. Z.; Dong, W. F.; Liu, W. Microfluidic Electroporation-Facilitated Synthesis of Erythrocyte Membrane-Coated Magnetic Nanoparticles for Enhanced Imaging-Guided Cancer Therapy. ACS Nano 2017, 11 (4), 3496– 3505,  DOI: 10.1021/acsnano.7b00133
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    34
    Microfluidic Electroporation-Facilitated Synthesis of Erythrocyte Membrane-Coated Magnetic Nanoparticles for Enhanced Imaging-Guided Cancer Therapy
    Rao, Lang; Cai, Bo; Bu, Lin-Lin; Liao, Qing-Quan; Guo, Shi-Shang; Zhao, Xing-Zhong; Dong, Wen-Fei; Liu, Wei
    ACS Nano (2017), 11 (4), 3496-3505CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    Biomimetic cell membrane-coated nanoparticles (CM-NPs) with superior biochem. properties have been broadly utilized for various biomedical applications. Currently, researchers primarily focus on using ultrasonic treatment and mech. extrusion to improve the synthesis of CM-NPs. In this work, we demonstrate that microfluidic electroporation can effectively facilitate the synthesis of CM-NPs. To test it, Fe3O4 magnetic nanoparticles (MNs) and red blood cell membrane-derived vesicles (RBC-vesicles) are infused into a microfluidic device. When the mixt. of MNs and RBC-vesicles flow through the electroporation zone, the elec. pulses can effectively promote the entry of MNs into RBC-vesicles. After that, the resulting RBC membrane-capped MNs (RBC-MNs) are collected from the chip and injected into exptl. animals to test the in vivo performance. Owing to the superior magnetic and photothermal properties of the MN cores and the long blood circulation characteristic of the RBC membrane shells, core-shell RBC-MNs were used for enhanced tumor magnetic resonance imaging (MRI) and photothermal therapy (PTT). Due to the completer cell membrane coating, RBC-MNs prepd. by microfluidic electroporation strategy exhibit significantly better treatment effect than the one fabricated by conventional extrusion. We believe the combination of microfluidic electroporation and CM-NPs provides an insight into the synthesis of bioinpired nanoparticles to improve cancer diagnosis and therapy.
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    Yu, G. T.; Rao, L.; Wu, H.; Yang, L. L.; Bu, L. L.; Deng, W. W.; Wu, L.; Nan, X.; Zhang, W. F.; Zhao, X. Z.; Liu, W.; Sun, Z. J. Myeloid-Derived Suppressor Cell Membrane-Coated Magnetic Nanoparticles for Cancer Theranostics by Inducing Macrophage Polarization and Synergizing Immunogenic Cell Death. Adv. Funct. Mater. 2018, 28 (37), 1801389,  DOI: 10.1002/adfm.201801389
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    Kondo, E.; Iioka, H.; Saito, K. Tumor-Homing Peptide and Its Utility for Advanced Cancer Medicine. Cancer Sci. 2021, 112 (6), 2118– 2125,  DOI: 10.1111/cas.14909
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    Tumor-homing peptide and its utility for advanced cancer medicine
    Kondo, Eisaku; Iioka, Hidekazu; Saito, Ken
    Cancer Science (2021), 112 (6), 2118-2125CODEN: CSACCM; ISSN:1349-7006. (Wiley-Blackwell)
    A review. Cell-penetrating peptides, such as antibodies, have gained great attention as tools for the development of specific delivery systems for payloads, which might be applied as non-invasive carriers in vivo. Among these, tumor-homing peptides recently have been studied for use in tumor medicine. Tumor-homing peptides are oligopeptides, usually consisting of 30 or fewer amino acids that are efficiently and specifically incorporated into tumor cells, suggesting their potential use in establishing novel non-invasive tumor imaging systems for diagnostic and therapeutic applications. Here, we briefly introduce the biol. characteristics of our tumor-homing peptides, focusing esp. on those developed using a random peptide library constructed using mRNA display technol. The advantage of the tumor-homing peptides is their biol. safety, given that these mols. do not show significant cytotoxicity against non-neoplastic cells; lack serious antigenicity, which alternatively might evoke unfavorable immune responses and inflammation in vivo; and are rapidly incorporated into target cells/tissues, with rates exceeding those seen for antibodies. Given their small size, tumor-homing peptides also are easy to modify and redesign. Based on these merits, tumor-homing peptides are expected to find wide application in various aspects of tumor medicine, including imaging diagnostics (eg, with dye-conjugated probes for direct visualization of invasive/metastatic tumor lesions in vivo) and therapeutics (eg, using peptide-drug conjugates [PDCs] for tumor targeting). Although further evidence will be required to demonstrate their practical utility, tumor-homing peptides are expected to show great potential as a next-generation bio-tool contributing to precision medicine for cancer patients.
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    Wada, A.; Terashima, T.; Kageyama, S.; Yoshida, T.; Narita, M.; Kawauchi, A.; Kojima, H. Efficient Prostate Cancer Therapy with Tissue-Specific Homing Peptides Identified by Advanced Phage Display Technology. Mol. Ther. - Oncolytics 2019, 12 (3), 138– 146,  DOI: 10.1016/j.omto.2019.01.001
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    37
    Efficient Prostate Cancer Therapy with Tissue-Specific Homing Peptides Identified by Advanced Phage Display Technology
    Wada, Akinori; Terashima, Tomoya; Kageyama, Susumu; Yoshida, Tetsuya; Narita, Mitsuhiro; Kawauchi, Akihiro; Kojima, Hideto
    Molecular Therapy--Oncolytics (2019), 12 (), 138-146CODEN: MTOHDL; ISSN:2372-7705. (Elsevier)
    Selective targeting of drugs to tumor cells is a key goal in oncol. Here, we performed an in vivo phage display to identify peptides that specifically target xenografted prostate cancer cells. This yielded three peptide candidates, LN1 (C-TGTPARQ-C), LN2 (C-KNSMFAT-C), and LN3 (C-TNKHSPK-C); each of these peptides was synthesized and evaluated for binding and biol. activity. LN1 showed the highest avidity for LNCaP prostate cancer cells in vitro and was thus administered to tumor-bearing mice to evaluate in vivo binding. Strikingly, LN1 specifically bound to the tumor tissue and exhibited very low reactivity with normal liver and kidney tissues. To demonstrate that LN1 could specifically deliver drugs to prostate cancer tissue, a therapeutic peptide, LN1-KLA (C-TGTPARQ-C-GGG-D[KLAKLAK]2), was prepd. and used to treat LNCaP cells in vitro and was also administered to tumor-bearing mice. The therapeutic peptide significantly suppressed growth of the cells both in vitro and in vivo. Our study shows that a selective homing peptide strategy could facilitate cell-specific targeting of therapeutics while avoiding adverse reactions in normal tissues.
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    Wang, L.; Wang, X.; Luo, J.; Wanjala, B. N.; Wang, C.; Chernova, N. A.; Engelhard, M. H.; Liu, Y.; Bae, I. T.; Zhong, C. J. Core-Shell-Structured Magnetic Ternary Nanocubes. J. Am. Chem. Soc. 2010, 132 (50), 17686– 17689,  DOI: 10.1021/ja1091084
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    Core-Shell-Structured Magnetic Ternary Nanocubes
    Wang, Ling-Yan; Wang, Xin; Luo, Jin; Wanjala, Bridgid N.; Wang, Chong-Min; Chernova, Natasha A.; Engelhard, Mark H.; Liu, Yao; Bae, In-Tae; Zhong, Chuan-Jian
    Journal of the American Chemical Society (2010), 132 (50), 17686-17689CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The authors report a novel core-shell-structured ternary nanocube of MnZn ferrite synthesized by controlling the reaction temp. and compn. in the absence of conventionally used reducing agents. The highly monodispersed core-shell structure consists of an Fe3O4 core and an MnZn Ferrite shell. The observation of a Moire pattern indicates that the core and the shell are two highly cryst. materials with slightly different lattice consts. that are rotated relative to each other by a small angle. The ternary core-shell nanocubes display magnetic properties regulated by a combination of the core-shell compn. and exhibit an increased coercivity and field-cooled/zero-field-cooled characteristics drastically different from those of regular MnZn ferrite nanoparticles. The ability to engineer the spatial nanostructures of ternary magnetic nanoparticles in terms of shape and compn. offers at.-level versatility in fine-tuning the nanoscale magnetic properties.
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    Tong, S.; Hou, S.; Ren, B.; Zheng, Z.; Bao, G. Self-Assembly of Phospholipid-PEG Coating on Nanoparticles through Dual Solvent Exchange. Nano Lett. 2011, 11 (9), 3720– 3726,  DOI: 10.1021/nl201978c
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    Self-Assembly of Phospholipid-PEG Coating on Nanoparticles through Dual Solvent Exchange
    Tong, Sheng; Hou, Si-Jian; Ren, Bin-Bin; Zheng, Zhi-Lan; Bao, Gang
    Nano Letters (2011), 11 (9), 3720-3726CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
    We coated nanoparticles including iron oxide nanoparticles and quantum dots with phospholipid-PEG using the newly developed dual solvent exchange method and demonstrated that, compared with the conventional film hydration method, the coating efficiency and quality of coated nanoparticles can be significantly improved. A better control of surface coating d. and the amt. of reactive groups on nanoparticle surface is achieved, allowing conjugation of different moieties with desirable surface concns., thus facilitating biomedical applications of nanoparticles.
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    De Pasquale, D.; Marino, A.; Tapeinos, C.; Pucci, C.; Rocchiccioli, S.; Michelucci, E.; Finamore, F.; McDonnell, L.; Scarpellini, A.; Lauciello, S.; Prato, M.; Larrañaga, A.; Drago, F.; Ciofani, G. Homotypic Targeting and Drug Delivery in Glioblastoma Cells through Cell Membrane-Coated Boron Nitride Nanotubes. Mater. Des. 2020, 192, 108742,  DOI: 10.1016/j.matdes.2020.108742
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    Homotypic targeting and drug delivery in glioblastoma cells through cell membrane-coated boron nitride nanotubes
    De Pasquale, Daniele; Marino, Attilio; Tapeinos, Christos; Pucci, Carlotta; Rocchiccioli, Silvia; Michelucci, Elena; Finamore, Francesco; McDonnell, Liam; Scarpellini, Alice; Lauciello, Simone; Prato, Mirko; Larranaga, Aitor; Drago, Filippo; Ciofani, Gianni
    Materials & Design (2020), 192 (), 108742CODEN: MADSD2; ISSN:0264-1275. (Elsevier Ltd.)
    Glioblastoma multiforme (GBM) is one of the most aggressive types of brain cancer, characterized by rapid progression, resistance to treatments, and low survival rates; the development of a targeted treatment for this disease is still today an unattained objective. Among the different strategies developed in the latest few years for the targeted delivery of nanotherapeutics, homotypic membrane-membrane recognition is one of the most promising and efficient. In this work, we present an innovative drug-loaded nanocarrier with improved targeting properties based on the homotypic recognition of GBM cells. The developed nanoplatform consists of boron nitride nanotubes (BNNTs) loaded with doxorubicin (Dox) and coated with cell membranes (CM) extd. from GBM cells (Dox-CM-BNNTs). We demonstrated as Dox-CM-BNNTs are able to specifically target and kill GBM cells in vitro, leaving unaffected healthy brain cells, upon successful crossing an in vitro blood-brain barrier model. The excellent targeting performances of the nanoplatform can be ascribed to the protein component of the membrane coating, and proteomic anal. of differently expressed membrane proteins present on the CM of GBM cells and of healthy astrocytes allowed the identification of potential candidates involved in the process of homotypic cancer cell recognition.
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    Pucci, C.; De Pasquale, D.; Marino, A.; Martinelli, C.; Lauciello, S.; Ciofani, G. Hybrid Magnetic Nanovectors Promote Selective Glioblastoma Cell Death through a Combined Effect of Lysosomal Membrane Permeabilization and Chemotherapy. ACS Appl. Mater. Interfaces 2020, 12 (26), 29037– 29055,  DOI: 10.1021/acsami.0c05556
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    Hybrid Magnetic Nanovectors Promote Selective Glioblastoma Cell Death through a Combined Effect of Lysosomal Membrane Permeabilization and Chemotherapy
    Pucci, Carlotta; De Pasquale, Daniele; Marino, Attilio; Martinelli, Chiara; Lauciello, Simone; Ciofani, Gianni
    ACS Applied Materials & Interfaces (2020), 12 (26), 29037-29055CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
    Glioblastoma multiforme is the most aggressive brain tumor, due to its high invasiveness and genetic heterogeneity. Moreover, the blood-brain barrier prevents many drugs from reaching a therapeutic concn. at the tumor site, and most of the chemotherapeutics lack in specificity toward cancer cells, accumulating in both healthy and diseased tissues, with severe side effects. Here, we present in vitro investigations on lipid-based nanovectors encapsulating a drug, nutlin-3a, and superparamagnetic iron oxide nanoparticles, to combine the proapoptotic action of the drug and the hyperthermia mediated by superparamagnetic iron oxide nanoparticles stimulated with an alternating magnetic field. The nanovectors are functionalized with the peptide angiopep-2 to induce receptor-mediated transcytosis through the blood-brain barrier and to target a receptor overexpressed by glioma cells. The glioblastoma multiforme targeting efficiency and the blood-brain barrier crossing abilities were tested through in vitro fluidic models, where different human cell lines were placed to mimic the tumor microenvironment. These nanovectors successfully cross the blood-brain barrier model, maintaining their targeting abilities for glioblastoma multiforme with minimal interaction with healthy cells. Moreover, we showed that nanovector-assisted hyperthermia induces a lysosomal membrane permeabilization that not only initiates a caspase-dependent apoptotic pathway, but also enhances the anticancer efficacy of the drug.
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    Fairley, N.; Fernandez, V.; Richard-Plouet, M.; Guillot-Deudon, C.; Walton, J.; Smith, E.; Flahaut, D.; Greiner, M.; Biesinger, M.; Tougaard, S.; Morgan, D.; Baltrusaitis, J. Systematic and Collaborative Approach to Problem Solving Using X-Ray Photoelectron Spectroscopy. Appl. Surf. Sci. Adv. 2021, 5 (March), 100112,  DOI: 10.1016/j.apsadv.2021.100112
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    Fang, C.; Veiseh, O.; Kievit, F.; Bhattarai, N.; Wang, F.; Stephen, Z.; Li, C.; Lee, D.; Ellenbogen, R. G.; Zhang, M. Functionalization of Iron Oxide Magnetic Nanoparticles with Targeting Ligands: Their Physicochemical Properties and in Vivo Behavior. Nanomedicine 2010, 5 (9), 1357– 1369,  DOI: 10.2217/nnm.10.55
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    Functionalization of iron oxide magnetic nanoparticles with targeting ligands: their physicochemical properties and in vivo behavior
    Fang, Chen; Veiseh, Omid; Kievit, Forrest; Bhattarai, Narayan; Wang, Freddy; Stephen, Zach; Li, Chun; Lee, Donghoon; Ellenbogen, Richard G.; Zhang, Miqin
    Nanomedicine (London, United Kingdom) (2010), 5 (9), 1357-1369CODEN: NLUKAC; ISSN:1743-5889. (Future Medicine Ltd.)
    Aim: To develop and evaluate two tumor-specific nanoprobes by functionalization of a polyethylene glycol-immobilized nanoparticle with arginine-glycine-aspartic acid (RGD) or chlorotoxin ligand that targets αvβ3 integrin and matrix metalloproteinase-2 receptors, resp. Materials & methods: The nanoprobes were made of iron oxide cores, biocompatible polymer coating, and surface-conjugated RGD or chlorotoxin peptide. The tumor-targeting specificity of the nanoprobes was evaluated both in vitro and in vivo. Results & discussion: Both nanoprobes were highly dispersive and exhibited excellent long-term stability in cell culture media. The RGD-conjugated nanoprobe displayed a strong initial accumulation near neovasculatures in tumors followed by quick clearance. Conversely, the chlorotoxin-enabled nanoprobe exhibited sustained accumulation throughout the tumor. Conclusion: These findings revealed the influence of the targeting ligands on the intratumoral distribution of the ligand-enabled nanoprobes. With flexible surface chem., our nanoparticle platform can be used in a modular fashion to conjugate biomols. for intended applications.
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  46. 46
    Shi, W.; Cao, X.; Liu, Q.; Zhu, Q.; Liu, K.; Deng, T.; Yu, Q.; Deng, W.; Yu, J.; Wang, Q.; Xu, X. Hybrid Membrane-Derived Nanoparticles for Isoliquiritin Enhanced Glioma Therapy. Pharmaceuticals 2022, 15 (9), 1059,  DOI: 10.3390/ph15091059
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    Hybrid Membrane-Derived Nanoparticles for Isoliquiritin Enhanced Glioma Therapy
    Shi, Wenwan; Cao, Xia; Liu, Qi; Zhu, Qin; Liu, Kai; Deng, Tianwen; Yu, Qingtong; Deng, Wenwen; Yu, Jiangnan; Wang, Qilong; Xu, Ximing
    Pharmaceuticals (2022), 15 (9), 1059CODEN: PHARH2; ISSN:1424-8247. (MDPI AG)
    Due to the obstruction and heterogeneity of the blood-brain barrier, the clin. treatment of glioma has been extremely difficult. Isoliquiritigenin (ISL) exhibits antitumor effects, but its low soly. and bioavailability limit its application potential. Herein, we established a nanoscale hybrid membrane-derived system composed of erythrocytes and tumor cells. By encapsulating ISL in hybrid membrane nanoparticles, ISL is expected to be enhanced for the targeting and long-circulation in gliomas therapy. We fused erythrocytes with human glioma cells U251 and extd. the fusion membrane via hypotension, termed as hybrid membrane (HM). HM-camouflaged ISL nanoparticles (ISL@HM NPs) were prepd. and featured with FT-IR, SEM, TEM, and DLS particle anal. As the results concluded, the ISL active pharmaceutical ingredients (APIs) were successfully encapsulated with HM membranes, and the NPs loading efficiency was 38.9 ± 2.99% under max. entrapment efficiency. By comparing the IC50 of free ISL and NPs, we verified that the soly. and antitumor effect of NPs was markedly enhanced. We also investigated the mechanism of the antitumor effect of ISL@HM NPs, which revealed a marked inhibition of tumor cell proliferation and promotion of senescence and apoptosis of tumor cells of the formulation. In addn., the FSC and WB results examd. the effects of different concns. of ISL@HM NPs on tumor cell disruption and apoptotic protein expression. Finally, it can be concluded that hybridized membrane-derived nanoparticles could prominently increase the soly. of insol. materials (as ISL), and also enhance its targeting and antitumor effect.
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    Wildeboer, R. R.; Southern, P.; Pankhurst, Q. A. On the Reliable Measurement of Specific Absorption Rates and Intrinsic Loss Parameters in Magnetic Hyperthermia Materials. J. Phys. D. Appl. Phys. 2014, 47 (49), 495003,  DOI: 10.1088/0022-3727/47/49/495003
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    On the reliable measurement of specific absorption rates and intrinsic loss parameters in magnetic hyperthermia materials
    Wildeboer, R. R.; Southern, P.; Pankhurst, Q. A.
    Journal of Physics D: Applied Physics (2014), 47 (49), 495003/1-495003/14, 14 pp.CODEN: JPAPBE; ISSN:0022-3727. (IOP Publishing Ltd.)
    A review. In the clin. application of magnetic hyperthermia, the heat generated by magnetic nanoparticles in an alternating magnetic field is used as a cancer treatment. The heating ability of the particles is quantified by the specific absorption rate (SAR), an extrinsic parameter based on the clin. response characteristic of power delivered per unit mass, and by the intrinsic loss parameter (ILP), an intrinsic parameter based on the heating capacity of the material. Even though both the SAR and ILP are widely used as comparative design parameters, they are almost always measured in non-adiabatic systems that make accurate measurements difficult. We present here the results of a systematic review of measurement methods for both SAR and ILP, leading to recommendations for a standardised, simple and reliable method for measurements using non-adiabatic systems. In a representative survey of 50 retrieved datasets taken from published papers, the derived SAR or ILP was found to be more than 5% overestimated in 24% of cases and more than 5% underestimated in 52% of cases.
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    Marino, A.; Camponovo, A.; Degl’Innocenti, A.; Bartolucci, M.; Tapeinos, C.; Martinelli, C.; De Pasquale, D.; Santoro, F.; Mollo, V.; Arai, S.; Suzuki, M.; Harada, Y.; Petretto, A.; Ciofani, G. Multifunctional Temozolomide-Loaded Lipid Superparamagnetic Nanovectors: Dual Targeting and Disintegration of Glioblastoma Spheroids by Synergic Chemotherapy and Hyperthermia Treatment. Nanoscale 2019, 11 (44), 21227– 21248,  DOI: 10.1039/C9NR07976A
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    Multifunctional temozolomide-loaded lipid superparamagnetic nanovectors: dual targeting and disintegration of glioblastoma spheroids by synergic chemotherapy and hyperthermia treatment
    Marino, Attilio; Camponovo, Alice; Degl'Innocenti, Andrea; Bartolucci, Martina; Tapeinos, Christos; Martinelli, Chiara; De Pasquale, Daniele; Santoro, Francesca; Mollo, Valentina; Arai, Satoshi; Suzuki, Madoka; Harada, Yoshie; Petretto, Andrea; Ciofani, Gianni
    Nanoscale (2019), 11 (44), 21227-21248CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
    Aiming at finding new solns. for fighting glioblastoma multiforme, one of the most aggressive and lethal human cancer, here an in vitro validation of multifunctional nanovectors for drug delivery and hyperthermia therapy is proposed. Hybrid magnetic lipid nanoparticles have been fully characterized and tested on a multi-cellular complex model resembling the tumor microenvironment. Investigations of cancer therapy based on a phys. approach (namely hyperthermia) and on a pharmaceutical approach (by exploiting the chemotherapeutic drug temozolomide) have been extensively carried out, by evaluating its antiproliferative and pro-apoptotic effects on 3D models of glioblastoma multiforme. A systematic study of transcytosis and endocytosis mechanisms has been moreover performed with multiple complimentary investigations, besides a detailed description of local temp. increments following hyperthermia application. Finally, an in-depth proteomic anal. corroborated the obtained findings, which can be summarized in the prepn. of a versatile, multifunctional, and effective nanoplatform able to overcome the blood-brain barrier and to induce powerful anti-cancer effects on in vitro complex models.
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    Avrutsky, M. I.; Troy, C. M. Caspase-9: A Multimodal Therapeutic Target with Diverse Cellular Expression in Human Disease. Front. Pharmacol. 2021, 12 (July), 1– 17,  DOI: 10.3389/fphar.2021.701301
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    Bruderer, R.; Bernhardt, O. M.; Gandhi, T.; Miladinović, S. M.; Cheng, L. Y.; Messner, S.; Ehrenberger, T.; Zanotelli, V.; Butscheid, Y.; Escher, C.; Vitek, O.; Rinner, O.; Reiter, L. Extending the Limits of Quantitative Proteome Profiling with Data-Independent Acquisition and Application to Acetaminophen-Treated Three-Dimensional Liver Microtissues. Mol. Cell. Proteomics 2015, 14 (5), 1400– 1410,  DOI: 10.1074/mcp.M114.044305
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    Extending the Limits of Quantitative Proteome Profiling with Data-Independent Acquisition and Application to Acetaminophen-Treated Three-Dimensional Liver Microtissues
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    Molecular & Cellular Proteomics (2015), 14 (5), 1400-1410CODEN: MCPOBS; ISSN:1535-9484. (American Society for Biochemistry and Molecular Biology)
    Our findings imply that DIA should be the preferred method for quant. protein profiling.
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    Tyanova, S.; Temu, T.; Sinitcyn, P.; Carlson, A.; Hein, M. Y.; Geiger, T.; Mann, M.; Cox, J. The Perseus Computational Platform for Comprehensive Analysis of (Prote)Omics Data. Nat. Methods 2016, 13 (9), 731– 740,  DOI: 10.1038/nmeth.3901
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    The Perseus computational platform for comprehensive analysis of (prote)omics data
    Tyanova, Stefka; Temu, Tikira; Sinitcyn, Pavel; Carlson, Arthur; Hein, Marco Y.; Geiger, Tamar; Mann, Matthias; Cox, Juergen
    Nature Methods (2016), 13 (9), 731-740CODEN: NMAEA3; ISSN:1548-7091. (Nature Publishing Group)
    A main bottleneck in proteomics is the downstream biol. anal. of highly multivariate quant. protein abundance data generated using mass-spectrometry-based anal. We developed the Perseus software platform (http://www.perseus-framework.org) to support biol. and biomedical researchers in interpreting protein quantification, interaction and post-translational modification data. Perseus contains a comprehensive portfolio of statistical tools for high-dimensional omics data anal. covering normalization, pattern recognition, time-series anal., cross-omics comparisons and multiple-hypothesis testing. A machine learning module supports the classification and validation of patient groups for diagnosis and prognosis, and it also detects predictive protein signatures. Central to Perseus is a user-friendly, interactive workflow environment that provides complete documentation of computational methods used in a publication. All activities in Perseus are realized as plugins, and users can extend the software by programming their own, which can be shared through a plugin store. We anticipate that Perseus's arsenal of algorithms and its intuitive usability will empower interdisciplinary anal. of complex large data sets.
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    Nica, V.; Sauer, H. M.; Embs, J.; Hempelmann, R. Calorimetric Method for the Determination of Curie Temperatures of Magnetic Nanoparticles in Dispersion. J. Phys.: Condens. Matter 2008, 20 (20), 204115,  DOI: 10.1088/0953-8984/20/20/204115
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    Calorimetric method for the determination of Curie temperatures of magnetic nanoparticles in dispersion
    Nica, V.; Sauer, H. M.; Embs, J.; Hempelmann, R.
    Journal of Physics: Condensed Matter (2008), 20 (20), 204115/1-204115/5CODEN: JCOMEL; ISSN:0953-8984. (Institute of Physics Publishing)
    MnxZn1-xFe2O4-based magnetic fluids with x = 0.1-0.9 were synthesized by copptn. The samples are heated in a radio frequency (rf) magnetic field using an radiofrequency generator at different powers, and the temp. is measured as function of time using an optical thermometer. The heating effect of the dispersed magnetic nanoparticles is proportional to the imaginary part of the dynamic magnetic susceptibility of the ferrofluid, a quantity that depends on the temp. through the magnetization of the ferrite nanoparticles and the Neel or Brownian relaxation times, resp. The authors propose an extrapolation method to actuate the Curie temps. of the dispersed magnetic nanoparticles. By appropriate fitting functions for (dT/dt) vs. T for both the heating and the cooling process, the authors deduce the Curie temp. of the samples under study. For MnxZn1-xFe2O4-based magnetic nanoparticles the Curie temps. decrease with increasing Zn content. They turn out to be lower than the literature values for bulk MnxZn1-xFe2O4, a phenomenon which is generally obsd. for phase transitions of nanocryst. materials.
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    Salazar-Alvarez, G.; Lidbaum, H.; López-Ortega, A.; Estrader, M.; Leifer, K.; Sort, J.; Suriñach, S.; Baró, M. D.; Nogués, J. Two-, Three-, and Four-Component Magnetic Multilayer Onion Nanoparticles Based on Iron Oxides and Manganese Oxides. J. Am. Chem. Soc. 2011, 133 (42), 16738– 16741,  DOI: 10.1021/ja205810t
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    Two-, Three-, and Four-Component Magnetic Multilayer Onion Nanoparticles Based on Iron Oxides and Manganese Oxides
    Salazar-Alvarez, German; Lidbaum, Hans; Lopez-Ortega, Alberto; Estrader, Marta; Leifer, Klaus; Sort, Jordi; Surinach, Santiago; Baro, Maria Dolors; Nogues, Josep
    Journal of the American Chemical Society (2011), 133 (42), 16738-16741CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Magnetic multilayered, onion-like, heterostructured nanoparticles are interesting model systems for studying magnetic exchange coupling phenomena. The authors synthesized heterostructured magnetic nanoparticles composed of two, three, or four components using iron oxide seeds for the subsequent deposition of manganese oxide. The MnO layer was allowed either to passivate fully in air to form an outer layer of Mn3O4 or to oxidize partially to form MnO|Mn3O4 double layers. Through control of the degree of passivation of the seeds, particles with up to four different magnetic layers can be obtained (i.e., FeO|Fe3O4|MnO|Mn3O4). Magnetic characterization of the samples confirmed the presence of the different magnetic layers.
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    Grosvenor, A. P.; Kobe, B. A.; Biesinger, M. C.; McIntyre, N. S. Investigation of Multiplet Splitting of Fe 2p XPS Spectra and Bonding in Iron Compounds. Surf. Interface Anal. 2004, 36 (12), 1564– 1574,  DOI: 10.1002/sia.1984
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    Investigation of multiplet splitting of Fe 2p XPS spectra and bonding in iron compounds
    Grosvenor, A. P.; Kobe, B. A.; Biesinger, M. C.; McIntyre, N. S.
    Surface and Interface Analysis (2004), 36 (12), 1564-1574CODEN: SIANDQ; ISSN:0142-2421. (John Wiley & Sons Ltd.)
    Ferrous (Fe2+) and ferric (Fe3+) compds. were studied by XPS to det. the usefulness of calcd. multiplet peaks to fit high-resoln. Fe 2p3/2 spectra from high-spin compds. The multiplets fit most spectra well, particularly when contributions attributed to surface peaks and shake-up satellites were included. This information was useful for fitting of the complex Fe 2p3/2 spectra for Fe3O4 where both Fe2+ and Fe3+ species are present. As the ionic bond character of the Fe-ligand bond increased, the binding energy assocd. with either the ferrous or ferric 2p3/2 photoelectron peak increased. This is due to the decrease in shielding of the Fe cation by the more increasingly electroneg. ligands. Also the difference in energy between a high-spin Fe 2p3/2 peak and its corresponding shake-up satellite peak increased as the electronegativity of the ligand increased. The extrinsic loss spectra for Fe oxides are reported; these are as characteristic of each species as are the photoelectron peaks.
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    Gupta, R. P.; Sen, S. K. Calculation of Multiplet Structure of Core p-Vacancy Levels. II. Phys. Rev. B 1975, 12 (1), 15– 19,  DOI: 10.1103/PhysRevB.12.15
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    Calculation of multiplet structure of core p-vacancy levels. II
    Gupta, R. P.; Sen, S. K.
    Physical Review B: Solid State (1975), 12 (1), 15-19CODEN: PLRBAQ; ISSN:0556-2805.
    The multiplet structure of core 2p-vacancy levels for 36 ions belonging to 3d transition metals were calcd. and their plots presented. Only the ground-state configuration 2p53dn (n = 1,...,9) is considered for each ion. The spin-orbit interaction was incorporated exactly, but the crystal-field effect is ignored. While there is general agreement with the available exptl. works, higher-energy resolution in x-ray-photoelectron measurements is necessary for detailed comparison of the spectra presented here. On the theor. side inclusion of crystal field appears to be important. One should go beyond single-configuration approxn. to have the obsd. satellite structure in 2p-x-ray-photoelectron spectra appear in the calcns.
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    McIntyre, N. S.; Zetaruk, D. G. X-Ray Photoelectron Spectroscopic Studies of Iron Oxides. Anal. Chem. 1977, 49 (11), 1521– 1529,  DOI: 10.1021/ac50019a016
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    X-ray photoelectron spectroscopic studies of iron oxides
    McIntyre, N. S.; Zetaruk, D. G.
    Analytical Chemistry (1977), 49 (11), 1521-9CODEN: ANCHAM; ISSN:0003-2700.
    Core line x-ray photoelectron (XP) spectra are reported for the iron compds. αFe2O3, γFe2O3, αFeOOH, NiFe2O4, CoFe2O4, Fe3O4, and FeO. Such XP spectra are of particular value in characterizing surface films contg. iron corrosion products. For the oxides and hydroxides FeOOH, FeO and Fe3O4, the obsd. chem. shift is sufficiently large to permit these species to be uniquely distinguished from other iron oxides. In Fe3O4, both ferrous and ferric oxidn. states are obsd. and their relative concns. can be detd. using spectral line fitting procedures. The oxides αFe2O3, γFe2O3, NiFe2O4, and CoFe2O4 have almost identical core binding energies, but the multiplet splitting patterns obsd. in their Fe(2p) core levels are sufficiently different to permit their use for characterization. The Fe(2p) multiplet pattern obsd. for αFe2O3 agrees well with splitting previously calcd. for the free Fe3+ ion. Valence band spectra for γFe2O3, αFe2O3, Fe3O4 and FeO are reported and band assignment are made. The effect of ion bombardment of iron oxide surfaces was studied and evidence for the redn. of ferric oxides to FeO is presented.
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    Pratt, A. R.; Muir, I. J.; Nesbitt, H. W. X-Ray Photoelectron and Auger Electron Spectroscopic Studies of Pyrrhotite and Mechanism of Air Oxidation. Geochim. Cosmochim. Acta 1994, 58 (2), 827– 841,  DOI: 10.1016/0016-7037(94)90508-8
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    X-ray photoelectron and Auger electron spectroscopic studies of pyrrhotite and mechanism of air oxidation
    Pratt, A. R.; Muir, I. J.; Nesbitt, H. W.
    Geochimica et Cosmochimica Acta (1994), 58 (2), 827-41CODEN: GCACAK; ISSN:0016-7037.
    Pyrrhotite (Fe7S8) fractured under high vacuum (10-7 Pa) and reacted with air for 6.5 and 50 h was analyzed using XPS and Auger Electron Spectroscopy (AES). XPS iron data from fresh surfaces indicate 32% Fe(III) and 68% Fe(II), both bonded to sulfur. The result agrees closely with stoichiometry which suggests 29% Fe(III) in the pyrrhotite studies. This is the first spectroscopic evidence to indicate Fe(III) in pyrrhotite. Sulfur is present primarily as monosulfide (S2-), with minor amts. of disulfide (S22-) and polysulfide (Sn2-). XPS examn. of 6.5 h air-oxidized surfaces indicates 58% Fe(III) and 42% Fe(II). Fe(III) is bonded to oxygen and most Fe(II) remains bonded to sulfur. XPS iron and oxygen data suggest a Fe(III)-oxyhydroxide to be the species that formed. Sulfur spectra demonstrate a range of oxidn. states from S2- (monosulfide) to S6+ (sulfate). AES compositional depth profiles of air-oxidized surfaces display three compositional zones. After 50 h of air oxidn. the outermost layer is less than 10 Å, oxygen-rich, and sulfur depleted. Immediately below the O-rich layer exists an Fe-deficient, S-rich layer that displays a continuous, gradual decrease in S/Fe from the O-rich zone to that of the unaltered pyrrhotite. Quantification of depth profiles utilizing the sequential layer sputtering model (SLS) indicate alteration trends correspond compositionally to FeO1.5, FeS2, Fe2S3, and Fe7S8. Compositional zones develop by electron and iron migration towards the oxidized surface. Mol. oxygen, initially taken onto the surface, is reduced to O2- probably by electron transfer from the pyrrhotite interior, and is facilitated by rapid electron exchange between Fe(III) and Fe(II) of the bulk solid. Vacancies inherent to nonstoichiometric pyrrhotite probably promote diffusion of iron to the surface resulting in the formation of iron oxyhydroxide species.
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    Biesinger, M. C.; Payne, B. P.; Grosvenor, A. P.; Lau, L. W. M.; Gerson, A. R.; Smart, R. S. C. Resolving Surface Chemical States in XPS Analysis of First Row Transition Metals, Oxides and Hydroxides: Cr, Mn, Fe, Co and Ni. Appl. Surf. Sci. 2011, 257 (7), 2717– 2730,  DOI: 10.1016/j.apsusc.2010.10.051
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    Resolving surface chemical states in XPS analysis of first row transition metals, oxides and hydroxides: Cr, Mn, Fe, Co and Ni
    Biesinger, Mark C.; Payne, Brad P.; Grosvenor, Andrew P.; Lau, Leo W. M.; Gerson, Andrea R.; Smart, Roger St. C.
    Applied Surface Science (2011), 257 (7), 2717-2730CODEN: ASUSEE; ISSN:0169-4332. (Elsevier B.V.)
    Chem. state x-ray photoelectron spectroscopic anal. of 1st row transition metals and their oxides and hydroxides is challenging due to the complexity of their 2p spectra resulting from peak asymmetries, complex multiplet splitting, shake-up and plasmon loss structure, and uncertain, overlapping binding energies. The previous paper in which the authors examd. Sc, Ti, V, Cu and Zn species, showed that all the values of the spectral fitting parameters for each specific species, i.e. binding energy (eV), full wide at half max. (FWHM) value (eV) for each pass energy, spin-orbit splitting values and asym. peak shape fitting parameters, are not all normally provided in the literature and data bases, and are necessary for reproducible, quant. chem. state anal. A more consistent, practical and effective approach to curve fitting was developed based on a combination of (1) std. spectra from quality ref. samples, (2) a survey of appropriate literature databases and/or a compilation of literature refs. and (3) specific literature refs. where fitting procedures are available. This paper extends this approach to the chem. states of Cr, Mn, Fe, Co and Ni metals, and various oxides and hydroxides where intense, complex multiplet splitting in many of the chem. states of these elements poses unique difficulties for chem. state anal. The curve fitting procedures proposed use the same criteria as proposed previously but with the addnl. complexity of fitting of multiplet split spectra which was done based on spectra of numerous ref. materials and theor. XPS modeling of these transition metal species. Binding energies, FWHM values, asym. peak shape fitting parameters, multiplet peak sepn. and peak area percentages are presented. The procedures developed can be used to remove uncertainties in the anal. of surface states in nanoparticles, corrosion, catalysis and surface-engineered materials.
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    Biesinger, M. C.; Lau, L. W. M.; Gerson, A. R.; Smart, R. S. C. Resolving Surface Chemical States in XPS Analysis of First Row Transition Metals, Oxides and Hydroxides: Sc, Ti, V, Cu and Zn. Appl. Surf. Sci. 2010, 257 (3), 887– 898,  DOI: 10.1016/j.apsusc.2010.07.086
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    Resolving surface chemical states in XPS analysis of first row transition metals, oxides and hydroxides: Sc, Ti, V, Cu and Zn
    Biesinger, Mark C.; Lau, Leo W. M.; Gerson, Andrea R.; Smart, Roger St. C.
    Applied Surface Science (2010), 257 (3), 887-898CODEN: ASUSEE; ISSN:0169-4332. (Elsevier B.V.)
    Chem. state x-ray photoelectron spectroscopic anal. of 1st row transition metals and their oxides and hydroxides is challenging due to the complexity of the 2p spectra resulting from peak asymmetries, complex multiplet splitting, shake-up and plasmon loss structure, and uncertain, overlapping binding energies. Current literature shows that all values necessary for reproducible, quant. chem. state anal. are usually not provided. A more consistent, practical and effective approach to curve-fitting the various chem. states in a variety of Sc, Ti, V, Cu and Zn metals, oxides and hydroxides is reported. The curve-fitting procedures proposed are based on a combination of (1) std. spectra from quality ref. samples, (2) a survey of appropriate literature databases and/or a compilation of the literature refs., and (3) specific literature refs. where fitting procedures are available. Binding energies, full-width at half max. (FWHM) values, spin-orbit splitting values, asym. peak-shape fitting parameters, and, for Cu and Zn, Auger parameters values are presented. The quantification procedure for Cu species details the use of the shake-up satellites for Cu(II)-contg. compds. and the exact binding energies of the Cu(0) and Cu(I) peaks. The use of the modified Auger parameter for Cu and Zn species allows for corroborating evidence when there is uncertainty in the binding energy assignment. These procedures can remove uncertainties in anal. of surface states in nano-particles, corrosion, catalysis and surface-engineered materials.
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    Tanuma, S.; Powell, C. J.; Penn, D. R. Electron Inelastic Mean Free Paths in Solids at Low Energies. J. Electron Spectrosc. Relat. Phenom. 1990, 52 (C), 285– 291,  DOI: 10.1016/0368-2048(90)85024-4
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    Tanuma, S.; Powell, C. J.; Penn, D. R.
    Journal of Electron Spectroscopy and Related Phenomena (1990), 52 (), 285-91CODEN: JESRAW; ISSN:0368-2048.
    Electron inelastic mean free path (IMFPs) were calcd. for 50-200 eV electrons in 31 materials (27 elements and 4 compds.). These calcns. extend those previously reported for 200-2000 eV electrons in the same materials but avoid an approxn. valid for electron energies above 200 eV. IMFP results are presented in this paper for magnesium, aluminum, silicon, nickel, copper, and gold. The IMFP dependence on electron energy in the range 50-200 eV varies considerably from material to material; these variations are assocd. with substantial differences in the electron energy-loss functions amongst the materials. The general IMFP formula derived earlier was extended to describe the calcd. IMFPs over the 50-2000 eV energy range.
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  61. 61
    Song, Q.; Zhang, Z. J. Controlled Synthesis and Magnetic Properties of Bimagnetic Spinel Ferrite CoFe2O4 and MnFe2O 4 Nanocrystals with Core-Shell Architecture. J. Am. Chem. Soc. 2012, 134 (24), 10182– 10190,  DOI: 10.1021/ja302856z
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    61
    Controlled Synthesis and Magnetic Properties of Bimagnetic Spinel Ferrite CoFe2O4 and MnFe2O4 Nanocrystals with Core-Shell Architecture
    Song, Qing; Zhang, Z. John
    Journal of the American Chemical Society (2012), 134 (24), 10182-10190CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    A combination of hard phase CoFe2O4 and soft phase MnFe2O4 as the bimagnetic nanocrystals in a core-shell architecture has been synthesized, and their magnetic properties have been systematically studied. Both HRTEM and EDS results confirmed the formation of bimagnetic core-shell structured nanocrystals. On the basis of the systematic and comparative studies of the magnetic properties of a mech. mixt. of pure CoFe2O4 and MnFe2O4 nanocrystals, chem. mixed Co1-xMnxFe2O4 nanocrystals, and bimagnetic core-shell CoFe2O4@MnFe2O4 and MnFe2O4@CoFe2O4 nanocrystals, the bimagnetic core-shell nanocrystals show very unique magnetic properties, such as the blocking temp. and coercivity. Our results show that the coercivity correlates with the vol. fraction of the soft phase as the theor. hard-soft phase model has suggested. Furthermore, switching the hard phase CoFe2O4 from the core to the shell shows great changes in the coercivity of the nanocrystals. The bimagnetic core-shell nanocrystals evidently demonstrate the rational design capability to sep. control the blocking temp. and the coercivity in magnetic nanocrystals by varying the materials, their combination, and the vol. ratio between the core and the shell and by switching hard or soft phase materials between the core and shell. Such controls via a bimagnetic core-shell architecture are highly desirable for magnetic nanocrystals in various applications.
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    Juhin, A.; López-Ortega, A.; Sikora, M.; Carvallo, C.; Estrader, M.; Estradé, S.; Peiró, F.; Baró, M. D.; Sainctavit, P.; Glatzel, P.; Nogués, J. Direct Evidence for an Interdiffused Intermediate Layer in Bi-Magnetic Core-Shell Nanoparticles. Nanoscale 2014, 6 (20), 11911– 11920,  DOI: 10.1039/C4NR02886D
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    Direct evidence for an interdiffused intermediate layer in bi-magnetic core-shell nanoparticles
    Juhin, Amelie; Lopez-Ortega, Alberto; Sikora, Marcin; Carvallo, Claire; Estrader, Marta; Estrade, Sonia; Peiro, Francesca; Baro, Maria Dolors; Sainctavit, Philippe; Glatzel, Pieter; Nogues, Josep
    Nanoscale (2014), 6 (20), 11911-11920CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
    Core-shell nanoparticles attract continuously growing interest due to their numerous applications, which are driven by the possibility of tuning their functionalities by adjusting structural and morphol. parameters. However, despite the crit. role interdiffused interfaces may have in the properties, these are usually only estd. in indirect ways. Here we directly evidence the existence of a 1.1 nm thick (Fe,Mn)3O4 interdiffused intermediate shell in nominally γ-Fe2O3-Mn3O4 core-shell nanoparticles using resonant inelastic X-ray scattering spectroscopy combined with magnetic CD (RIXS-MCD). This recently developed magneto-spectroscopic probe exploits the unique advantages of hard X-rays (i.e., chem. selectivity, bulk sensitivity, and low self-absorption at the K pre-edge) and can be advantageously combined with transmission electron microscopy and electron energy loss spectroscopy to quant. elucidate the buried internal structure of complex objects. The detailed information on the structure of the nanoparticles allows understanding the influence of the interface quality on the magnetic properties.
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    Kubisztal, M.; Kubisztal, J.; Karolus, M.; Prusik, K.; Haneczok, G. Evolution of Frozen Magnetic State in Co-Precipitated ZnδCo1-δFe2O4 (0 ≤ δ ≤ 1) Ferrite Nanopowders. J. Magn. Magn. Mater. 2018, 454, 368– 374,  DOI: 10.1016/j.jmmm.2018.02.001
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    Evolution of frozen magnetic state in co-precipitated ZnδCo1-δFe2O4 (0 ≤ δ ≤ 1) ferrite nanopowders
    Kubisztal, M.; Kubisztal, J.; Karolus, M.; Prusik, K.; Haneczok, G.
    Journal of Magnetism and Magnetic Materials (2018), 454 (), 368-374CODEN: JMMMDC; ISSN:0304-8853. (Elsevier B.V.)
    The evolution of frozen magnetic state of ZnδCo1-δFe2O4 (0 ≤ δ ≤ 1) ferrite nanoparticles was studied by applying vibrating sample magnetometer measurements in temp. range 5-350 K and magnetic fields up to 7 T. It was shown that gradual conversion from the inverse spinel (δ = 0) to the normal one (δ = 1.0) is correlated with a drop of freezing temp. Tf (corresponding to blocking of mean magnetic moment of the system) from 238 K (δ = 0) to 9 K (δ = 1.0) and with a decrease of magnetic anisotropy const. K1 from about 8 · 105 J/m3 to about 3 · 105 J/m3. The percolation threshold predicted for bulk ferrites at 1 - δ ≈ 0.33 was obsd. as a significant weakness of ferrimagnetic coupling. In this case magnetization curves, detd. according to the zero field cooling protocol, reveal two distinct maxima indicating that the system splits into two assemblies with specific ions distribution between A and B sites.
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    Gneveckow, U.; Jordan, A.; Scholz, R.; Brüß, V.; Waldöfner, N.; Ricke, J.; Feussner, A.; Hildebrandt, B.; Rau, B.; Wust, P. Description and Characterization of the Novel Hyperthermia- and Thermoablation-System MFH®300F for Clinical Magnetic Fluid Hyperthermia. Med. Phys. 2004, 31 (6), 1444– 1451,  DOI: 10.1118/1.1748629
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    64
    Description and characterization of the novel hyperthermia- and thermoablation-system MFH 300F for clinical magnetic fluid hyperthermia
    Gneveckow Uwe; Jordan Andreas; Scholz Regina; Bruss Volker; Waldofner Norbert; Ricke Jens; Feussner Annelie; Hildebrandt Bert; Rau Beate; Wust Peter
    Medical physics (2004), 31 (6), 1444-51 ISSN:0094-2405.
    Magnetic fluid hyperthermia (MFH) is a new approach to deposit heat power in deep tissues by overcoming limitations of conventional heat treatments. After infiltration of the target tissue with nanosized magnetic particles, the power of an alternating magnetic field is transformed into heat. The combination of the 100 kHz magnetic field applicator MFH 300F and the magnetofluid (MF), which both are designed for medical use, is investigated with respect to its dosage recommendations and clinical applicability. We found a magnetic field strength of up to 18 kA/m in a cylindrical treatment area of 20 cm diameter and aperture height up to 300 mm. The specific absorption rate (SAR) can be controlled directly by the magnetic field strength during the treatment. The relationship between magnetic field strength and the iron normalized SAR (SAR(Fe)) is only slightly depending on the concentration of the MF and can be used for planning the target SAR. The achievable energy absorption rates of the MF distributed in the tissue is sufficient for either hyperthermia or thermoablation. The fluid has a visible contrast in therapeutic concentrations on a CT scanner and can be detected down to 0.01 g/l Fe in the MRI. The system has proved its capability and practicability for heat treatment in deep regions of the human body.
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    Liu, X.; Zhang, Y.; Wang, Y.; Zhu, W.; Li, G.; Ma, X.; Zhang, Y.; Chen, S.; Tiwari, S.; Shi, K.; Zhang, S.; Fan, H. M.; Zhao, Y. X.; Liang, X. J. Comprehensive Understanding of Magnetic Hyperthermia for Improving Antitumor Therapeutic Efficacy. Theranostics 2020, 10 (8), 3793– 3815,  DOI: 10.7150/thno.40805
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    Comprehensive understanding of magnetic hyperthermia for improving antitumor therapeutic efficacy
    Liu, Xiaoli; Zhang, Yifan; Wang, Yanyun; Zhu, Wenjing; Li, Galong; Ma, Xiaowei; Zhang, Yihan; Chen, Shizhu; Tiwari, Shivani; Shi, Kejian; Zhang, Shouwen; Fan, Hai Ming; Zhao, Yong Xiang; Liang, Xing-Jie
    Theranostics (2020), 10 (8), 3793-3815CODEN: THERDS; ISSN:1838-7640. (Ivyspring International Publisher)
    A review. Magnetic hyperthermia (MH) has been introduced clin. as an alternative approach for the focal treatment of tumors. MH utilizes the heat generated by the magnetic nanoparticles (MNPs) when subjected to an alternating magnetic field (AMF). It has become an important topic in the nanomedical field due to their multitudes of advantages towards effective antitumor therapy such as high biosafety, deep tissue penetration, and targeted selective tumor killing. However, in order for MH to progress and to realize its paramount potential as an alternative choice for cancer treatment, tremendous challenges have to be overcome. Thus, the efficiency of MH therapy needs enhancement. In its recent 60-yr of history, the field of MH has focused primarily on heating using MNPs for therapeutic applications. Increasing the thermal conversion efficiency of MNPs is the fundamental strategy for improving therapeutic efficacy. Recently, emerging exptl. evidence indicates that MNPs-MH produces nano-scale heat effects without macroscopic temp. rise. A deep understanding of the effect of this localized induction heat for the destruction of subcellular/cellular structures further supports the efficacy of MH in improving therapeutic therapy. In this review, the currently available strategies for improving the antitumor therapeutic efficacy of MNPs-MH will be discussed. Firstly, the recent advancements in engineering MNP size, compn., shape, and surface to significantly improve their energy dissipation rates will be explored. Secondly, the latest studies depicting the effect of local induction heat for selectively disrupting cells/intracellular structures will be examd. Thirdly, strategies to enhance the therapeutics by combining MH therapy with chemotherapy, radiotherapy, immunotherapy, photothermal/photodynamic therapy (PDT), and gene therapy will be reviewed. Lastly, the prospect and significant challenges in MH-based antitumor therapy will be discussed. This review is to provide a comprehensive understanding of MH for improving antitumor therapeutic efficacy, which would be of utmost benefit towards guiding the users and for the future development of MNPs-MH towards successful application in medicine.
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    Noh, S. H.; Na, W.; Jang, J. T.; Lee, J. H.; Lee, E. J.; Moon, S. H.; Lim, Y.; Shin, J. S.; Cheon, J. Nanoscale Magnetism Control via Surface and Exchange Anisotropy for Optimized Ferrimagnetic Hysteresis. Nano Lett. 2012, 12 (7), 3716– 3721,  DOI: 10.1021/nl301499u
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    Nanoscale magnetism control via surface and exchange anisotropy for optimized ferrimagnetic hysteresis
    Noh, Seung-hyun; Na, Wonjun; Jang, Jung-tak; Lee, Jae-Hyun; Lee, Eun Jung; Moon, Seung Ho; Lim, Yongjun; Shin, Jeon-Soo; Cheon, Jinwoo
    Nano Letters (2012), 12 (7), 3716-3721CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
    With the aim of controlling nanoscale magnetism, we demonstrate an approach encompassing concepts of surface and exchange anisotropy while reflecting size, shape, and structural hybridization of nanoparticles. We visualize that cube has higher magnetization value than sphere with highest coercivity at 60 nm. Its hybridization into core-shell (CS) structure brings about a 14-fold increase in the coercivity with an exceptional energy conversion of magnetic field into thermal energy of 10600 W/g, the largest reported to date. Such capability of the CS-cube is highly effective for drug resistant cancer cell treatment.
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    Balk, M.; Haus, T.; Band, J.; Unterweger, H.; Schreiber, E.; Friedrich, R. P.; Alexiou, C.; Gostian, A. O. Cellular Spion Uptake and Toxicity in Various Head and Neck Cancer Cell Lines. Nanomaterials 2021, 11 (3), 726,  DOI: 10.3390/nano11030726
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    Cellular SPION uptake and toxicity in various head and neck cancer cell lines
    Balk, Matthias; Haus, Theresa; Band, Julia; Unterweger, Harald; Schreiber, Eveline; Friedrich, Ralf P.; Alexiou, Christoph; Gostian, Antoniu-Oreste
    Nanomaterials (2021), 11 (3), 726CODEN: NANOKO; ISSN:2079-4991. (MDPI AG)
    Superparamagnetic iron oxide nanoparticles (SPIONs) feature distinct magnetic properties that make them useful and effective tools for various diagnostic, therapeutic and theranostic applications. In particular, their use in magnetic drug targeting (MDT) promises to be an effective approach for the treatment of various diseases such as cancer. At the cellular level, SPION uptake, along with SPION-mediated toxicity, represents the most important prerequisite for successful application. Thus, the present study dets. SPION uptake, toxicity and biocompatibility in human head and neck tumor cell lines of the tongue, pharynx and salivary gland. Using magnetic susceptibility measurements, microscopy, at. emission spectroscopy, flow cytometry, and plasma coagulation, we analyzed the magnetic properties, cellular uptake and biocompatibility of two different SPION types in the presence and absence of external magnetic fields. Incubation of cells with lauric acid and human serum albumin-coated nanoparticles (SPIONLA-HSA) resulted in substantial particle uptake with low cytotoxicity. In contrast, uptake of lauric acid-coated nanoparticles (SPIONLA) was substantially increased but accompanied by higher toxicity. The presence of an external magnetic field significantly increased cellular uptake of both particles, although cytotoxicity was not significantly increased in any of the cell lines. SPIONs coated with lauric acid and/or human serum albumin show different patterns of uptake and toxicity in response to an external magnetic field. Consequently, the results indicate the potential use of SPIONs as vehicles for MDT in head and neck cancer.
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    Chen, L.; Hong, W.; Ren, W.; Xu, T.; Qian, Z.; He, Z. Recent Progress in Targeted Delivery Vectors Based on Biomimetic Nanoparticles. Signal Transduct. Target. Ther. 2021, 6, 225,  DOI: 10.1038/s41392-021-00631-2
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    Recent progress in targeted delivery vectors based on biomimetic nanoparticles
    Chen Li; Hong Weiqi; Ren Wenyan; Xu Ting; Qian Zhiyong; He Zhiyao; Xu Ting; He Zhiyao
    Signal transduction and targeted therapy (2021), 6 (1), 225 ISSN:.
    Over the past decades, great interest has been given to biomimetic nanoparticles (BNPs) since the rise of targeted drug delivery systems and biomimetic nanotechnology. Biological vectors including cell membranes, extracellular vesicles (EVs), and viruses are considered promising candidates for targeted delivery owing to their biocompatibility and biodegradability. BNPs, the integration of biological vectors and functional agents, are anticipated to load cargos or camouflage synthetic nanoparticles to achieve targeted delivery. Despite their excellent intrinsic properties, natural vectors are deliberately modified to endow multiple functions such as good permeability, improved loading capability, and high specificity. Through structural modification and transformation of the vectors, they are pervasively utilized as more effective vehicles that can deliver contrast agents, chemotherapy drugs, nucleic acids, and genes to target sites for refractory disease therapy. This review summarizes recent advances in targeted delivery vectors based on cell membranes, EVs, and viruses, highlighting the potential applications of BNPs in the fields of biomedical imaging and therapy industry, as well as discussing the possibility of clinical translation and exploitation trend of these BNPs.
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    Li, J.; Wang, X.; Zheng, D.; Lin, X.; Wei, Z.; Zhang, D.; Li, Z.; Zhang, Y.; Wu, M.; Liu, X. Cancer Cell Membrane-Coated Magnetic Nanoparticles for MR/NIR Fluorescence Dual-Modal Imaging and Photodynamic Therapy. Biomater. Sci. 2018, 6 (7), 1834– 1845,  DOI: 10.1039/C8BM00343B
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    Cancer cell membrane-coated magnetic nanoparticles for MR/NIR fluorescence dual-modal imaging and photodynamic therapy
    Li, Jiong; Wang, Xuandong; Zheng, Dongye; Lin, Xinyi; Wei, Zuwu; Zhang, Da; Li, Zhuanfang; Zhang, Yun; Wu, Ming; Liu, Xiaolong
    Biomaterials Science (2018), 6 (7), 1834-1845CODEN: BSICCH; ISSN:2047-4849. (Royal Society of Chemistry)
    Theranostic nanoprobes integrated with dual-modal imaging and therapeutic functions, such as photodynamic therapy (PDT), have exhibited significant potency in cancer treatments due to their high imaging accuracy and non-invasive advantages for cancer elimination. However, biocompatibility and highly efficient accumulation of these nanoprobes in tumor are still unsatisfactory for clin. application. In this study, a photosensitizer -loaded magnetic nanobead with surface further coated with a layer of cancer cell membrane (SSAP-Ce6@CCM) was designed to improve the biocompatibility and cellular uptake and ultimately achieve enhanced MR/NIR fluorescence imaging and PDT efficacy. Compared with similar nanobeads without CCM coating, SSAP-Ce6@CCM showed significantly enhanced cellular uptake, as evidenced by Prussian blue staining, confocal laser scanning microscopy (CLSM) and flow cytometric anal. Consequently, SSAP-Ce6@CCM displayed a more distinct MR/NIR imaging ability and more obvious photo-cytotoxicity towards cancer cells under 670 nm laser irradn. Furthermore, the enhanced PDT effect benefited from the surface coating of cancer cell membrane was demonstrated in SMMC-7721 tumor-bearing mice through tumor growth observation and tumor tissue pathol. examn. Therefore, this CCM-disguised nanobead that integrated the abilities of MR/NIR fluorescence dual-modal imaging and photodynamic therapy might be a promising theranostic platform for tumor treatment.
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    Weiss, I. M.; Muth, C.; Drumm, R.; Kirchner, H. O. K. Thermal Decomposition of the Amino Acids Glycine, Cysteine, Aspartic Acid, Asparagine, Glutamic Acid, Glutamine, Arginine and Histidine. BMC Biophys. 2018, 11, 2,  DOI: 10.1186/s13628-018-0042-4
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    70
    Thermal decomposition of the amino acids glycine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine, arginine and histidine
    Weiss, Ingrid M.; Muth, Christina; Drumm, Robert; Kirchner, Helmut O. K.
    BMC Biophysics (2018), 11 (), 2/1-2/15CODEN: BBMIG8; ISSN:2046-1682. (BioMed Central Ltd.)
    The pathways of thermal instability of amino acids have been unknown. New mass spectrometric data allow unequivocal quant. identification of the decompn. products. Calorimetry, thermogravimetry and mass spectrometry were used to follow the thermal decompn. of the eight amino acids G, C, D, N, E, Q, R and H between 185 °C and 280 °C. Endothermic heats of decompn. between 72 and 151 kJ/mol are needed to form 12 to 70% volatile products. This process is neither melting nor sublimation. With exception of cysteine they emit mainly H2O, some NH3 and no CO2. Cysteine produces CO2 and little else. The reactions are described by polynomials, AA → a NH3 + b H2O + c CO2 + d H2S + e residue, with integer or half integer coeffs. The solid monomol. residues are rich in peptide bonds. Eight of the 20 std. amino acids decomp. at well-defined, characteristic temps., in contrast to commonly accepted knowledge. Products of decompn. are simple. The novel quant. results emphasize the impact of water and cyclic condensates with peptide bonds and put constraints on hypotheses of the origin, state and stability of amino acids in the range between 200 °C and 300 °C.
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    Athanasoulia, I. G.; Tarantili, P. A. Preparation and Characterization of Polyethylene Glycol/Poly(L-Lactic Acid) Blends. Pure Appl. Chem. 2017, 89 (1), 141– 152,  DOI: 10.1515/pac-2016-0919
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    Preparation and characterization of polyethylene glycol/poly(L-lactic acid) blends
    Athanasoulia, Ioanna-Georgia; Tarantili, Petroula A.
    Pure and Applied Chemistry (2017), 89 (1), 141-152CODEN: PACHAS; ISSN:0033-4545. (Walter de Gruyter, Inc.)
    The effect of incorporation of poly(ethylene glycol) (PEG) on thermomech. and hydrophilicity properties of poly(L-lactic acid) (PLLA) was investigated. PEG/PLLA blends, contg. 10, 20, 30 and 40 wt.% PEG, were prepd. by melt-extrusion in a co-rotating twin-screw extruder. By DSC anal., it was obsd. that the Tg of PLLA phase in PEG/PLLA blends decreased accompanied by a significant decrease in Tcc and increase in their melting enthalpy. Therefore, the addn. of PEG enhances the crystn. ability of PLLA phase due to its lubricating effect which increased mobility of PLLA chains. From TGA it was obsd. that low concns. of PEG (10 & 20 wt.%) increase the Tonset of thermal degrdn., probably due to improved heat resistance of the cryst. phase. At higher PEG content, the Tonset decreases, as the lubricating effect becomes the controlling mechanism for the initiation of degrdn. process. Decrease in tensile strength and modulus was recorded esp. in PLLA blends with PEG content higher than 20 wt.%. The elongation at break decreases reaching a max. at 20 wt.% PEG and then dropped again. To investigate the effect of PEG on the wetting ability of PLLA, water contact angle measurements were performed. The results indicate that the introduction of PEG lowers the contact angle values in PEG/PLLA film surfaces, as compared to pure PLLA, suggesting improved hydrophilic properties.
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    Xia, X.; Yang, M.; Wang, Y.; Zheng, Y.; Li, Q.; Chen, J.; Xia, Y. Quantifying the Coverage Density of Poly(Ethylene Glycol) Chains on the Surface of Gold Nanostructures. ACS Nano 2012, 6 (1), 512– 522,  DOI: 10.1021/nn2038516
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    Quantifying the Coverage Density of Poly(ethylene glycol) Chains on the Surface of Gold Nanostructures
    Xia, Xiaohu; Yang, Miaoxin; Wang, Yucai; Zheng, Yiqun; Li, Qingge; Chen, Jingyi; Xia, Younan
    ACS Nano (2012), 6 (1), 512-522CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    The coverage d. of poly(ethylene glycol) (PEG) is a key parameter in detg. the efficiency of PEGylation, a process pivotal to in vivo delivery and targeting of nanomaterials. Here we report four complementary methods for quantifying the coverage d. of PEG chains on various types of Au nanostructures by using a model system based on HS-PEG-NH2 with different mol. wts. Specifically, the methods involve reactions with fluorescamine and ninhydrin, as well as labeling with fluorescein isothiocyanate (FITC) and Cu2+ ions. The first two methods use conventional amine assays to measure the no. of unreacted HS-PEG-NH2 mols. left behind in the soln. after incubation with the Au nanostructures. The other two methods involve coupling between the terminal -NH2 groups of adsorbed -S-PEG-NH2 chains and FITC or a ligand for Cu2+ ion, and thus pertain to the "active" -NH2 groups on the surface of a Au nanostructure. We found that the coverage d. decreased as the length of PEG chains increased. A stronger binding affinity of the initial capping ligand to the Au surface tended to reduce the PEGylation efficiency by slowing down the ligand exchange process. For the Au nanostructures and capping ligands we have tested, the PEGylation efficiency decreased in the order of citrate-capped nanoparticles > PVP-capped nanocages ≈ CTAC-capped nanoparticles » CTAB-capped nanorods, where PVP, CTAC, and CTAB stand for poly(vinyl pyrrolidone), cetyltrimethylammonium chloride, and cetyltrimethylammonium bromide, resp.
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    Miller, I.; Min, M.; Yang, C.; Tian, C.; Gookin, S.; Carter, D.; Spencer, S. L. Ki67 Is a Graded Rather than a Binary Marker of Proliferation versus Quiescence. Cell Rep. 2018, 24 (5), 1105– 1112,  DOI: 10.1016/j.celrep.2018.06.110
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    Ki67 is a Graded Rather than a Binary Marker of Proliferation versus Quiescence
    Miller, Iain; Min, Mingwei; Yang, Chen; Tian, Chengzhe; Gookin, Sara; Carter, Dylan; Spencer, Sabrina L.
    Cell Reports (2018), 24 (5), 1105-1112.e5CODEN: CREED8; ISSN:2211-1247. (Cell Press)
    Ki67 staining is widely used as a proliferation indicator in the clinic, despite poor understanding of this protein's function or dynamics. Here, we track Ki67 levels under endogenous control in single cells over time and find that Ki67 accumulation occurs only during S, G2, and M phases. Ki67 is degraded continuously in G1 and G0 phases, regardless of the cause of entry into G0/quiescence. Consequently, the level of Ki67 during G0 and G1 in individual cells is highly heterogeneous and depends on how long an individual cell has spent in G0. Thus, Ki67 is a graded rather than a binary marker both for cell-cycle progression and time since entry into quiescence.
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    Nguyen, T. N.; Chebbi, I.; Le Fèvre, R.; Guyot, F.; Alphandéry, E. Non-Pyrogenic Highly Pure Magnetosomes for Efficient Hyperthermia Treatment of Prostate Cancer. Appl. Microbiol. Biotechnol. 2023, 107 (4), 1159– 1176,  DOI: 10.1007/s00253-022-12247-9
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    Non-pyrogenic highly pure magnetosomes for efficient hyperthermia treatment of prostate cancer
    Nguyen, Tieu Ngoc; Chebbi, Imene; Le Fevre, Raphael; Guyot, Francois; Alphandery, Edouard
    Applied Microbiology and Biotechnology (2023), 107 (4), 1159-1176CODEN: AMBIDG; ISSN:0175-7598. (Springer International Publishing AG)
    We report the fabrication of highly pure magnetosomes that are synthesized by magnetotactic bacteria (MTB) using pharmaceutically compatible growth media, i.e., without compds. of animal origin (yeast exts.), carcinogenic, mutagenic, or toxic for reprodn. (CMR) products, and other heavy metals than iron. To enable magnetosome medical applications, these growth media are reduced and amended compared with media commonly used to grow these bacteria. Furthermore, magnetosomes are made non-pyrogenic by being extd. from these micro-organisms and heated above 400°C to remove and denature bacterial org. material and produce inorg. magnetosome minerals. To be stabilized, these minerals are further coated with citric acid to yield M-CA, leading to fully reconstructed chains of magnetosomes. The heating properties and anti-tumor activity of highly pure M-CA are then studied by bringing M-CA into contact with PC3-Luc tumor cells and by exposing such assembly to an alternating magnetic field (AMF) of 42 mT and 195 kHz during 30 min. While in the absence of AMF, M-CA are obsd. to be non-cytotoxic, they result in a 35% decrease in cell viability following AMF application. The treatment efficacy can be assocd. with a specific absorption rate (SAR) value of M-CA, which is relatively high in cellular environment, i.e., SARcell = 253 ± 11 W/gFe, while being lower than the M-CA SAR value measured in water, i.e., SARwater = 1025 ± 194 W/gFe, highlighting that a redn. in the Brownian contribution to the SAR value in cellular environment does not prevent efficient tumor cell destruction with these nanoparticles.
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  75. 75
    Calatayud, M. P.; Soler, E.; Torres, T. E.; Campos-Gonzalez, E.; Junquera, C.; Ibarra, M. R.; Goya, G. F. Cell Damage Produced by Magnetic Fluid Hyperthermia on Microglial BV2 Cells. Sci. Rep. 2017, 7 (1), 1– 16,  DOI: 10.1038/s41598-017-09059-7
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    75
    Butyrate-producing bacteria supplemented in vitro to Crohn's disease patient microbiota increased butyrate production and enhanced intestinal epithelial barrier integrity
    Geirnaert, Annelies; Calatayud, Marta; Grootaert, Charlotte; Laukens, Debby; Devriese, Sarah; Smagghe, Guy; De Vos, Martine; Boon, Nico; Van de Wiele, Tom
    Scientific Reports (2017), 7 (1), 1-14CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
    The management of the dysbiosed gut microbiota in inflammatory bowel diseases (IBD) is gaining more attention as a novel target to control this disease. Probiotic treatment with butyrate-producing bacteria has therapeutic potential since these bacteria are depleted in IBD patients and butyrate has beneficial effects on epithelial barrier function and overall gut health. However, studies assessing the effect of probiotic supplementation on microbe-microbe and host-microbe interactions are rare. In this study, butyrate-producing bacteria (three mono-species and one multispecies mix) were supplemented to the fecal microbial communities of ten Crohn's disease (CD) patients in an in vitro system simulating the mucus- and lumen-assocd. microbiota. Effects of supplementation in short-chain fatty acid levels, bacterial colonization of mucus environment and intestinal epithelial barrier function were evaluated. Treatment with F. prausnitzii and the mix of six butyrate-producers significantly increased the butyrate prodn. by 5-11 mol%, and colonization capacity in mucus- and lumen-assocd. CD microbiota. Treatments with B. pullicaecorum 25-3T and the mix of six butyrate-producers improved epithelial barrier integrity in vitro. This study provides proof-of-concept data for the therapeutic potential of butyrate-producing bacteria in CD and supports the future preclin. development of a probiotic product contg. butyrate-producing species.
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    Crezee, J.; Franken, N. A. P.; Oei, A. L. Hyperthermia-Based Anti-Cancer Treatments. Cancers 2021, 13, 1240,  DOI: 10.3390/cancers13061240
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    Sabirzhanov, B.; Stoica, B. A.; Hanscom, M.; Piao, C. S.; Faden, A. I. Over-Expression of HSP70 Attenuates Caspase-Dependent and Caspase-Independent Pathways and Inhibits Neuronal Apoptosis. J. Neurochem. 2012, 123 (4), 542– 554,  DOI: 10.1111/j.1471-4159.2012.07927.x
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    77
    Over-expression of HSP70 attenuates caspase-dependent and caspase-independent pathways and inhibits neuronal apoptosis
    Sabirzhanov, Boris; Stoica, Bogdan A.; Hanscom, Marie; Piao, Chun-Shu; Faden, Alan I.
    Journal of Neurochemistry (2012), 123 (3&4), 542-554CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)
    HSP70 is a member of the family of heat-shock proteins that are known to be up-regulated in neurons following injury and/or stress. HSP70 over-expression has been linked to neuroprotection in multiple models, including neurodegenerative disorders. In contrast, less is known about the neuroprotective effects of HSP70 in neuronal apoptosis and with regard to modulation of programmed cell death (PCD) mechanisms in neurons. The authors examd. the effects of HSP70 over-expression by transfection with HSP70-expression plasmids in primary cortical neurons and the SH-SY5Y neuronal cell line using four independent models of apoptosis: etoposide, staurosporine, C2-ceramide, and β-Amyloid. In these apoptotic models, neurons transfected with the HSP70 construct showed significantly reduced induction of nuclear apoptotic markers and/or cell death. Furthermore, the authors demonstrated that HSP70 binds and potentially inactivates Apoptotic protease-activating factor 1, as well as apoptosis-inducing factor, key mols. involved in development of caspase-dependent and caspase-independent PCD, resp. Markers of caspase-dependent PCD, including active caspase-3, caspase-9, and cleaved PARP were attenuated in neurons over-expressing HSP70. These data indicate that HSP70 protects against neuronal apoptosis and suggest that these effects reflect, at least in part, to inhibition of both caspase-dependent and caspase-independent PCD pathways.
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    Calderwood, S. K.; Gong, J. Heat Shock Proteins Promote Cancer: It’s a Protection Racket. Trends Biochem. Sci. 2016, 41 (4), 311– 323,  DOI: 10.1016/j.tibs.2016.01.003
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    Heat Shock Proteins Promote Cancer: It's a Protection Racket
    Calderwood, Stuart K.; Gong, Jianlin
    Trends in Biochemical Sciences (2016), 41 (4), 311-323CODEN: TBSCDB; ISSN:0968-0004. (Elsevier Ltd.)
    Heat shock proteins (HSP) are expressed at high levels in cancer and form a fostering environment that is essential for tumor development. Here, we review the recent data in this area, concg. mainly on Hsp27, Hsp70, and Hsp90. The overriding role of HSPs in cancer is to stabilize the active functions of overexpressed and mutated cancer genes. Thus, elevated HSPs are required for many of the traits that underlie the morbidity of cancer, including increased growth, survival, and formation of secondary cancers. In addn., HSPs participate in the evolution of cancer treatment resistance. HSPs are also released from cancer cells and influence malignant properties by receptor-mediated signaling. Current data strongly support efforts to target HSPs in cancer treatment.
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    Moulin, M.; Arrigo, A. P. Caspases Activation in Hyperthermia-Induced Stimulation of TRAIL Apoptosis. Cell Stress Chaperones 2008, 13 (3), 313– 326,  DOI: 10.1007/s12192-008-0027-3
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    Caspases activation in hyperthermia-induced stimulation of TRAIL apoptosis
    Moulin, Maryline; Arrigo, Andre-Patrick
    Cell Stress & Chaperones (2008), 13 (3), 313-326CODEN: CSCHFG; ISSN:1355-8145. (Springer)
    In leukemia cells, hyperthermia enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. The phenomenon is caspase-dependent and results in membrane changes leading to an increased recognition of TRAIL death receptors by TRAIL. Because either caspase-2 or an apical proteolytic event has been recently proposed to act as an initiator of the cell death mechanism induced by heat shock, we have investigated the hierarchy of caspase activation in cells exposed to the combined heat shock plus TRAIL treatment. We report here that caspases-2, -3, and -8 were the first caspases to be activated. As expected, caspase-8 is required and indispensable during the initiation of this death signaling. Caspase-2 may also participate in the phenomenon but, in contrast to caspase-8, its presence appears dispensable because its depletion by small interfering RNA is devoid of effects. Our observations also suggest a role of caspase-3 and of a particular cleaved form of this caspase during the early signals of heat shock plus TRAIL-induced apoptosis.
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  80. 80
    Court, K. A.; Hatakeyama, H.; Wu, S. Y.; Lingegowda, M. S.; Rodríguez-Aguayo, C.; López-Berestein, G.; Ju-Seog, L.; Rinaldi, C.; Juan, E. J.; Sood, A. K.; Torres-Lugo, M. HSP70 Inhibition Synergistically Enhances the Effects of Magnetic Fluid Hyperthermia in Ovarian Cancer. Mol. Cancer Ther. 2017, 16 (5), 966– 976,  DOI: 10.1158/1535-7163.MCT-16-0519
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    80
    HSP70 Inhibition Synergistically Enhances the Effects of Magnetic Fluid Hyperthermia in Ovarian Cancer
    Court, Karem A.; Hatakeyama, Hiroto; Wu, Sherry Y.; Lingegowda, Mangala S.; Rodriguez-Aguayo, Cristian; Liopez-Berestein, Gabriel; Lee, Ju-Seog; Rinaldi, Carlos; Juan, Eduardo J.; Sood, Anil K.; Torres-Lugo, Madeline
    Molecular Cancer Therapeutics (2017), 16 (5), 966-976CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)
    Hyperthermia has been investigated as a potential treatment for cancer. However, specificity in hyperthermia application remains a significant challenge. Magnetic fluid hyperthermia (MFH) may be an alternative to surpass such a challenge, but implications of MFH at the cellular level are not well understood. Therefore, the present work focused on the examn. of gene expression after MFH treatment and using such information to identify target genes that when inhibited could produce an enhanced therapeutic outcome after MFH. Genomic analyzes were performed using ovarian cancer cells exposed to MFH for 30 min at 43°C, which revealed that heat shock protein (HSP) genes, including HSPA6, were upregulated. HSPA6 encodes the Hsp70, and its expression was confirmed by PCR in HeyA8 and A2780cp20 ovarian cancer cells. Two strategies were investigated to inhibit Hsp70-related genes, siRNA and Hsp70 protein function inhibition by 2-phenylethyenesulfonamide (PES). Both strategies resulted in decreased cell viability following exposure to MFH. Combination index was calcd. for PES treatment reporting a synergistic effect. In vivo efficacy expts. with HSPA6 siRNA and MFH were performed using the A2780cp20 and HeyA8 ovarian cancer mouse models. A significantly redn. in tumor growth rate was obsd. with combination therapy. PES and MFH efficacy were also evaluated in the HeyA8 i.p. tumor model, and resulted in robust antitumor effects. This work demonstrated that HSP70 inhibition combination with MFH generate a synergistic effect and could be a promising target to enhance MFH therapeutic outcomes in ovarian cancer. Mol Cancer Ther; 16(5); 966-76. 2017 AACR.
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    Şen, D.; Emanet, M.; Ciofani, G. Nanotechnology-Based Strategies to Evaluate and Counteract Cancer Metastasis and Neoangiogenesis. Adv. Healthc. Mater. 2021, 10 (10), 1– 30,  DOI: 10.1002/adhm.202002163
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    Soenen, S. J. H.; Himmelreich, U.; Nuytten, N.; De Cuyper, M. Cytotoxic Effects of Iron Oxide Nanoparticles and Implications for Safety in Cell Labelling. Biomaterials 2011, 32 (1), 195– 205,  DOI: 10.1016/j.biomaterials.2010.08.075
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    Cytotoxic effects of iron oxide nanoparticles and implications for safety in cell labelling
    Soenen Stefaan J H; Himmelreich Uwe; Nuytten Nele; De Cuyper Marcel
    Biomaterials (2011), 32 (1), 195-205 ISSN:.
    The in vitro labelling of cultured cells with iron oxide nanoparticles (NPs) is a frequent practice in biomedical research. To date, the potential cytotoxicity of these particles remains an issue of debate. In the present study, 4 different NP types (dextran-coated Endorem, carboxydextran-coated Resovist, lipid-coated magnetoliposomes (MLs) and citrate-coated very small iron oxide particles (VSOP)) are tested on a variety of cell types, being C17.2 neural progenitor cells, PC12 rat pheochromocytoma cells and human blood outgrowth endothelial cells. Using different NP concentrations, the effect of the NPs on cell morphology, cytoskeleton, proliferation, reactive oxygen species, functionality, viability and cellular homeostasis is investigated. Through a systematic study, the safe concentrations for every particle type are determined, showing that MLs can lead up to 67.37 ± 5.98 pg Fe/cell whereas VSOP are the most toxic particles and only reach 18.65 ± 2.07 pg Fe/cell. Using these concentrations, it is shown that for MRI up to 500 cells/μl labelled with VSOP are required to efficiently visualize in an agar phantom in contrast to only 50 cells/μl for MLs and 200 cells/μl for Endorem and Resovist. These results highlight the importance of in-depth cytotoxic evaluation of cell labelling studies as at non-toxic concentrations, some particles appear to be less suitable for the MR visualization of labelled cells.
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    Mulens-Arias, V.; Rojas, J. M.; Sanz-ortega, L.; Portilla, Y.; Pérez-yagüe, S.; Barber, D. F. Polyethylenimine-Coated Superparamagnetic Iron Oxide Nanoparticles Impair in vitro and in vivo Angiogenesis ☆,☆☆,☆☆☆. Nanomedicine Nanotechnology, Biol. Med. 2019, 21, 102063,  DOI: 10.1016/j.nano.2019.102063
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    83
    Polyethylenimine-coated superparamagnetic iron oxide nanoparticles impair in vitro and in vivo angiogenesis
    Mulens-Arias Vladimir; Rojas Jose Manuel; Sanz-Ortega Laura; Portilla Yadileiny; Perez-Yague Sonia; Barber Domingo F
    Nanomedicine : nanotechnology, biology, and medicine (2019), 21 (), 102063 ISSN:.
    Endothelial cells are essential to tumor vascularization and impairing their activity can potentially limit tumor growth. Since polyethylenimine (PEI)-coated superparamagnetic iron oxide nanoparticles (SPIONs) are bioactive nanosystems that modulate inflammatory macrophage responses and limit tumor cell invasion, we evaluated their effects on endothelial cell angiogenesis. PEI-SPION triggered proinflammatory gene profiles in a murine endothelial cell line and in primary human umbilical cord vein endothelial cells (HUVECs). These nanoparticles impaired endothelial cell migration and inhibited HUVEC tube formation. Magnetically tumor-targeted PEI-SPIONs reduced tumor vessel numbers and promoted intratumor macrophage infiltration in a tumor xenograft model. PEI-SPION treatment impaired M2 macrophage-promoted tube formation and affected HUVEC cytoskeleton by limiting Src and Cortactin activation. These mechanisms could contribute to PEI-SPION in vitro and in vivo antiangiogenic potential. These data confirm that PEI-SPION administration and application of a localized magnetic field could offer an affordable anti-angiogenic anti-tumoral targeted treatment that would complement other therapies.
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    Wu, V. M.; Huynh, E.; Tang, S.; Uskoković, V. Brain and Bone Cancer Targeting by a Ferrofluid Composed of Superparamagnetic Iron-Oxide/Silica/Carbon Nanoparticles (Earthicles). Acta Biomater. 2019, 88, 422– 447,  DOI: 10.1016/j.actbio.2019.01.064
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    84
    Brain and bone cancer targeting by a ferrofluid composed of superparamagnetic iron-oxide/silica/carbon nanoparticles (earthicles)
    Wu, Victoria M.; Huynh, Eric; Tang, Sean; Uskokovic, Vuk
    Acta Biomaterialia (2019), 88 (), 422-447CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)
    Nanoparticles were synthesized hydrothermally and characterized using range of spectroscopic, diffractometric, hydrodynamic and electron microscopy techniques. Double coating on SPIONs affected no. of physicochem. and biol. properties, including colloidal stability and cancer targeting efficacy. Nanoparticles decreased viability of glioblastoma and osteosarcoma cells and tumors more than that of their primary and non-transformed analogs. They showed greater preference for cancer cells because of higher rate of uptake by these cells and pronounced adherence to cancer cell membrane. Even in ultralow alternate magnetic field, nanoparticles generated sufficient heat to cause tumor death. Nanoparticles in MDCK-MDR1 BBB model caused mislocalization of claudin-1 at tight junctions, underexpression of ZO-1 and no effect on occludin-1 and transepithelial resistance. Nanoparticles were detected in basolateral compartments and examn. of LAMP1 demonstrated that nanoparticles escaped lysosome, traversed BBB transcellularly and localized to optic lobes of third instar larval brains of D. melanogaster. Passage was noninvasive and caused no adverse systemic effects to animals. These nanoparticulate ferrofluids preferentially bind to cancer cells and, hence, exhibit greater toxicity in these cells compared to primary cells. They are also effective against solid tumors in vitro, can cross BBB in Drosophila, and are nontoxic based on developmental studies of flies raised in ferrofluid-infused media.
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    Hildebrandt, B.; Wust, P.; Ahlers, O.; Dieing, A.; Sreenivasa, G.; Kerner, T.; Felix, R.; Riess, H. The Cellular and Molecular Basis of Hyperthermia. Crit. Rev. Oncol. Hematol. 2002, 43 (1), 33– 56,  DOI: 10.1016/S1040-8428(01)00179-2
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    The cellular and molecular basis of hyperthermia
    Hildebrandt Bert; Wust Peter; Ahlers Olaf; Dieing Annette; Sreenivasa Geetha; Kerner Thoralf; Felix Roland; Riess Hanno
    Critical reviews in oncology/hematology (2002), 43 (1), 33-56 ISSN:1040-8428.
    In oncology, the term 'hyperthermia' refers to the treatment of malignant diseases by administering heat in various ways. Hyperthermia is usually applied as an adjunct to an already established treatment modality (especially radiotherapy and chemotherapy), where tumor temperatures in the range of 40-43 degrees C are aspired. In several clinical phase-III trials, an improvement of both local control and survival rates have been demonstrated by adding local/regional hyperthermia to radiotherapy in patients with locally advanced or recurrent superficial and pelvic tumors. In addition, interstitial hyperthermia, hyperthermic chemoperfusion, and whole-body hyperthermia (WBH) are under clinical investigation, and some positive comparative trials have already been completed. In parallel to clinical research, several aspects of heat action have been examined in numerous pre-clinical studies since the 1970s. However, an unequivocal identification of the mechanisms leading to favorable clinical results of hyperthermia have not yet been identified for various reasons. This manuscript deals with discussions concerning the direct cytotoxic effect of heat, heat-induced alterations of the tumor microenvironment, synergism of heat in conjunction with radiation and drugs, as well as, the presumed cellular effects of hyperthermia including the expression of heat-shock proteins (HSP), induction and regulation of apoptosis, signal transduction, and modulation of drug resistance by hyperthermia.
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    Jordan, A.; Scholz, R.; Maier-Hauff, K.; Johannsen, M.; Wust, P.; Nadobny, J.; Schirra, H.; Schmidt, H.; Deger, S.; Loening, S.; Lanksch, W.; Felix, R. Presentation of a New Magnetic Field Therapy System for the Treatment of Human Solid Tumors with Magnetic Fluid Hyperthermia. J. Magn. Magn. Mater. 2001, 225 (1–2), 118– 126,  DOI: 10.1016/S0304-8853(00)01239-7
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    86
    Presentation of a new magnetic field therapy system for the treatment of human solid tumors with magnetic fluid hyperthermia
    Jordan, A.; Scholz, R.; Maier-Hauff, K.; Johannsen, M.; Wust, P.; Nadobny, J.; Schirra, H.; Schmidt, H.; Deger, S.; Loening, S.; Lanksch, W.; Felix, R.
    Journal of Magnetism and Magnetic Materials (2001), 225 (1-2), 118-126CODEN: JMMMDC; ISSN:0304-8853. (Elsevier Science B.V.)
    Magnetic fluid hyperthermia (MFH) selectively heats up tissue by coupling a.c. (AC) magnetic fields to targeted magnetic fluids, so that boundaries of different conductive tissues do not interfere with power absorption. In this paper, a new AC magnetic field therapy system for clin. application of MFH is described. With optimized magnetic nanoparticle prepns. it will be used for target-specific glioblastoma and prostate carcinoma therapy.
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    Shi, F.; Ma, M.; Zhai, R.; Ren, Y.; Li, K.; Wang, H.; Xu, C.; Huang, X.; Wang, N.; Zhou, F.; Yao, W. Overexpression of Heat Shock Protein 70 Inhibits Epithelial-Mesenchymal Transition and Cell Migration Induced by Transforming Growth Factor-β in A549 Cells. Cell Stress Chaperones 2021, 26 (3), 505– 513,  DOI: 10.1007/s12192-021-01196-3
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    87
    Overexpression of heat shock protein 70 inhibits epithelial-mesenchymal transition and cell migration induced by transforming growth factor-β in A549 cells
    Shi, Fengxian; Ma, Mingze; Zhai, Ruonan; Ren, Yanan; Li, Ke; Wang, Hang; Xu, Chunyan; Huang, Xiaowen; Wang, Na; Zhou, Fang; Yao, Wu
    Cell Stress & Chaperones (2021), 26 (3), 505-513CODEN: CSCHFG; ISSN:1355-8145. (Springer)
    Heat shock protein 70 (HSP70) is a key member of the HSP family that contributes to a pre-cancerous environment; however, its role in lung cancer remains poorly understood. The present study used geranylgeranylacetone (GGA) to induce HSP70 expression, and transforming growth factor-β (TGF-β) was used to construct an epithelial-mesenchymal transition (EMT) model by stimulating A549 cells in vitro. Western Blot was performed to detect protein levels of NADPH oxidase 4 (NOX4) and the EMT-assocd. proteins E-cadherin and vimentin both before and after HSP70 expression. Cell morphol. changes were obsd., and the effect of HSP70 on cell migration ability was detected via the wound healing. The results demonstrated that GGA at 50 and 200μmol/L could significantly induce HSP70 expression in A549 cells (P < 0.05). Furthermore, HSP70 induced by 200μmol/L GGA significantly inhibited the changes of E-cadherin, vimentin, and cell morphol. induced by TGF-β (P < 0.05), while HSP70 induced by 50μmol/L GGA did not. The results of the wound healing assay indicated that 200μmol/L GGA significantly inhibited A549 cell migration induced by TGF-β. Taken together, the results of the present study demonstrated that overexpression of HSP70 inhibited the TGF-β induced EMT process and changed the cell morphol. and migratory ability induced by TGF-β in A549 cells.
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    Liang, C. Negative Regulation of Autophagy. Cell Death Differ. 2010, 17 (12), 1807– 1815,  DOI: 10.1038/cdd.2010.115
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    Negative regulation of autophagy
    Liang, C.
    Cell Death and Differentiation (2010), 17 (12), 1807-1815CODEN: CDDIEK; ISSN:1350-9047. (Nature Publishing Group)
    A review. Autophagy is an evolutionarily conserved catabolic process that involves the invagination and degrdn. of cytoplasmic components through an autophagosomelysosome track. Autophagy functions as a quality control of cellular milieu and is implicated in a wide variety of pathol. conditions. However, excessive or imbalanced autophagic flux may also be assocd. with cellular toxicity and may potentially contribute to the development of pathol. conditions. Just as all membrane trafficking systems need to constantly strike a balance in their level of activation and inhibition to ensure proper spatial and temporal delivery of their cargo, autophagy must also be tightly regulated. Here, we provide an overview of the current knowledge regarding the neg. regulation of mammalian autophagy in an effort to understand its physiol. relevance and potential clin. importance. Cell Death and Differentiation (2010) 17, 1807-1815; doi:10.1038/cdd.2010.115; published online 24 Sept. 2010.
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    Winkler, J.; Abisoye-Ogunniyan, A.; Metcalf, K. J.; Werb, Z. Concepts of Extracellular Matrix Remodelling in Tumour Progression and Metastasis. Nat. Commun. 2020, 11 (1), 1– 19,  DOI: 10.1038/s41467-020-18794-x
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    Day, E. K.; Sosale, N. G.; Lazzara, M. J. Cell Signaling Regulation by Protein Phosphorylation: A Multivariate, Heterogeneous, and Context-Dependent Process. Curr. Opin. Biotechnol. 2016, 40, 185– 192,  DOI: 10.1016/j.copbio.2016.06.005
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    Cell signaling regulation by protein phosphorylation: a multivariate, heterogeneous, and context-dependent process
    Day, Evan K.; Sosale, Nisha G.; Lazzara, Matthew J.
    Current Opinion in Biotechnology (2016), 40 (), 185-192CODEN: CUOBE3; ISSN:0958-1669. (Elsevier B.V.)
    Proper spatiotemporal regulation of protein phosphorylation in cells and tissues is required for normal development and homeostasis, but aberrant protein phosphorylation regulation leads to various diseases. The study of signaling regulation by protein phosphorylation is complicated in part by the sheer scope of the kinome and phosphoproteome, dependence of signaling protein functionality on cellular localization, and the complex multivariate relationships that exist between protein phosphorylation dynamics and the cellular phenotypes they control. Addnl. complexities arise from the ability of microenvironmental factors to influence phosphorylation-dependent signaling and from the tendency for some signaling processes to occur heterogeneously among cells. These considerations should be taken into account when measuring cell signaling regulation by protein phosphorylation.
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    Li, B.; Dou, S. X.; Yuan, J. W.; Liu, Y. R.; Li, W.; Ye, F.; Wang, P. Y.; Li, H. Intracellular Transport Is Accelerated in Early Apoptotic Cells. Proc. Natl. Acad. Sci. U. S. A. 2018, 115 (48), 12118– 12123,  DOI: 10.1073/pnas.1810017115
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    Intracellular transport is accelerated in early apoptotic cells
    Li, Bo; Dou, Shuo-Xing; Yuan, Jing-Wen; Liu, Yu-Ru; Li, Wei; Ye, Fangfu; Wang, Peng-Ye; Li, Hui
    Proceedings of the National Academy of Sciences of the United States of America (2018), 115 (48), 12118-12123CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Intracellular transport of cellular proteins and organelles is crit. for establishing and maintaining intracellular organization and cell physiol. Apoptosis is a process of programmed cell death with dramatic changes in cell morphol. and organization, during which signaling mols. are transported between different organelles within the cells. However, how the intracellular transport changes in cells undergoing apoptosis remains unknown. Here, we study the dynamics of intracellular transport by using the single-particle tracking method and find that both directed and diffusive motions of endocytic vesicles are accelerated in early apoptotic cells. With careful elimination of other factors involved in the intracellular transport, the reason for the acceleration is attributed to the elevation of ATP concn. More importantly, we show that the accelerated intracellular transport is crit. for apoptosis, and apoptosis is delayed when the dynamics of intracellular transport is regulated back to the normal level. Our results demonstrate the important role of transport dynamics in apoptosis and shed light on the apoptosis mechanism from a phys. perspective.
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    West, A. K. V.; Wullkopf, L.; Christensen, A.; Leijnse, N.; Tarp, J. M.; Mathiesen, J.; Erler, J. T.; Oddershede, L. B. Dynamics of Cancerous Tissue Correlates with Invasiveness. Sci. Rep. 2017, 7, 1– 11,  DOI: 10.1038/srep43800
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    Induced Pluripotent Stem Cell-Derived Neural Stem Cell Therapy Enhances Recovery in an Ischemic Stroke Pig Model
    Baker, Emily W.; Platt, Simon R.; Lau, Vivian W.; Grace, Harrison E.; Holmes, Shannon P.; Wang, Liya; Duberstein, Kylee Jo; Howerth, Elizabeth W.; Kinder, Holly A.; Stice, Steve L.; Hess, David C.; Mao, Hui; West, Franklin D.
    Scientific Reports (2017), 7 (1), 1-15CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
    Induced pluripotent stem cell-derived neural stem cells (iNSCs) have significant potential as an autologous, multifunctional cell therapy for stroke, which is the primary cause of long term disability in the United States and the second leading cause of death worldwide. Here we show that iNSC transplantation improves recovery through neuroprotective, regenerative, and cell replacement mechanisms in a novel ischemic pig stroke model. Longitudinal multiparametric magnetic resonance imaging (MRI) following iNSC therapy demonstrated reduced changes in white matter integrity, cerebral blood perfusion, and brain metab. in the infarcted tissue. The obsd. tissue level recovery strongly correlated with decreased immune response, enhanced neuronal protection, and increased neurogenesis. iNSCs differentiated into neurons and oligodendrocytes with indication of long term integration. The robust recovery response to iNSC therapy in a translational pig stroke model with increased predictive potential strongly supports that iNSCs may be the critically needed therapeutic for human stroke patients.
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  • Abstract

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    Figure 1

    Figure 1. Schematic illustration of coating and functionalization procedures of BMNPs and TMNPs: Fe3O4@Co0.5Zn0.5Fe2O4, soft–hard (SH); Fe3O4@Co0.5Zn0.5Fe2O4@MnFe2O4, soft–hard–soft (SHS); Fe3O4@Mn0.5Zn0.5Fe2O4, soft–soft (SS); (c) Fe3O4@Mn0.5Zn0.5Fe2O4@CoFe2O4, soft–soft–hard (SSH).

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    Figure 2

    Figure 2. Representative BF-TEM images of (a) SH, (b) SHS, (c) SS, and (d) SSH MNPs. The insets represent the magnified TEM image of corresponding samples. (e) BF-TEM image and corresponding EFTEM elemental maps for the SSH sample. EFTEM mapping demonstrates the presence of Fe, Zn, Mn, and Co. (f) X-ray diffraction patterns of pristine samples (SH, SHS, SS, and SSH MNPs).

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    Figure 3

    Figure 3. (a) Magnetic curves at room temperature of pristine samples (SH, SHS, SS, and SSH MNPs). The inset evidences the coercivity values. (b) Heating profile of ferrofluid samples (L-SH, L-SHS, L-SS, and L-SSH MNPs) exposed to AMF (f = 97.5 kHz, B = 20 mT, H = 15.9 kA/m; MNP concentration 5 mg/mL).

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    Figure 4

    Figure 4. BF-TEM micrographs of functionalized samples: (a) LN1-L-SSH MNPs, (b) negative-stained CM-L-SSH MNPs, and (c) negative-stained CM-LN1-L-SSH MNPs. DLS measurements: (d) hydrodynamic size distribution and (e) Z-potential before (L-SSH MNPs) and after functionalization (CM-L-SSH, CM-LN1-L-SSH, and CM-LN1-L-SSH MNPs).

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    Figure 5

    Figure 5. (a) Representative confocal images of PC-3 cultures incubated for 72 h with 250 μg/mL of MNPs (L-SSH, LN1-L-SSH, CM-L-SSH, and CM-LN1-L-SSH MNPs). F-actin in red, MNPs in green, and nuclei in blue. (b) ICP-OES elemental quantification of Fe (green), Zn (pink), Mn (gray), and Co (yellow) in PC-3 cells treated with the different MNPs.

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    Figure 6

    Figure 6. (a) Representative confocal laser scanning microscopy imaging of Ki-67 expression in PC-3 cells in the considered experimental classes. Nuclei in blue, Ki-67 in green, and F-actin in red. (b) In red, % of cells normalized to controls. In green, % of Ki-67-positive cells (Ki-67+).

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    Figure 7

    Figure 7. Flow cytometry analysis of apoptosis/necrosis: (a) representative flow cytometer scatter plots of propidium iodide vs annexin V-FITC. The populations of healthy, early apoptotic, late apoptotic, and necrotic cells have been highlighted in black, green, blue, and red, respectively. (b) Quantitative evaluation.

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    Figure 8

    Figure 8. (a) Expression of hsp70 in PC-3 cells upon magnetothermal stimulation: representative confocal laser scanning microscopy imaging (nuclei in blue, hsp70 in green, F-actin in red). (b) Average intensity of the hsp70 signal in the cells for each experimental condition (* p < 0.05).

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    Figure 9

    Figure 9. Activation of the caspase-9 apoptotic pathway upon acute stimulation with magnetic hyperthermia (“CM-LN1-L-SSH MNPs + AMF”). (a) Representative distributions of the cell fluorescent signal emission. Caspase-9-negative (−) and -positive (+) cells are highlighted in light blue and light red, respectively. (b) Quantitative evaluation of flow cytometry data for each experimental condition (* p < 0.05).

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    Figure 10

    Figure 10. Cell migration upon acute magnetothermal stimulation. (a) Representative images of PC-3 cells stained with calcein at t = 0 h and t = 24 h of cell migration. (b) % of gap size measured in each experimental class (* p < 0.05).

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    Figure 11

    Figure 11. Proteomic analysis: (a) principal component analysis (PCA) for 4 independent experiments in “Control” (blue cross), “Control + AMF” (orange square), “CM-LN1-L-SSH MNPs” (magenta circles), and “CM-LN1-L-SSH MNPs + AMF” (rhombuses in olive green color) treatments; (b) volcano plot and GO keywords regarding the “Control + AMF vs Control”, “CM-LN1-L-SSH MNPs vs Control”, and “CM-LN1-L-SSH MNPs + AMF vs Control” comparisons; upregulated and downregulated pathways are highlighted in green and red, respectively.

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  • References

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      Ca-Doped MgFe2O4 Nanoparticles for Magnetic Hyperthermia and Their Cytotoxicity in Normal and Cancer Cell Lines
      Manohar, Ala; Vijayakanth, Vembakam; Vattikuti, S. V. Prabhakar; Manivasagan, Panchanathan; Jang, Eue-Soon; Chintagumpala, Krishnamoorthi; Kim, Ki Hyeon
      ACS Applied Nano Materials (2022), 5 (4), 5847-5856CODEN: AANMF6; ISSN:2574-0970. (American Chemical Society)
      Localized magnetic hyperthermia (LMHT) cancer therapy is a much-anticipated technique along with immunotherapy. LMHT can be used as an independent or adjunct therapy to increase the efficacy of radiation and chemotherapy. The superparamagnetic nanoparticles (SPNPs) create LMHT by the electron magnetic spin relaxation (EMR) mechanism in nanocolloids. Magnetic nanoparticles of MgFe2O4 doped with different concns. of Ca2+ ions were designed to find sp. heating efficiency in magnetic hyperthermia (MHT) for applications in cancer therapy. Ca2+-substituted MgFe2O4 (CaxMg1-xFe2O4, x = 0.1, 0.3, and 0.5) nanoparticles with cubic spinel shapes and significant sizes were synthesized using high b.p. org. solvents. The heating efficiency or specific loss power (SLP) was detd. using a calorimetric method under various amplitudes of the magnetic field. The best shape with a particular size range for nanoparticles dispersed in deionized (DI) water carriers producing the optimum heating efficiency was specified. The CaxMg1-xFe2O4 (x = 0.1, 0.3, and 0.5) nanoparticles were investigated for in vitro cytotoxicity in normal cells (the mouse muscle fibroblast cell line BLO-11 and the mouse embryonic fibroblast cell line NIH 3T3) and human cancer cells (breast cancer cell line MDA-MB-23 and prostate cancer cell line PC-3) in terms of cell viability. The excellent heating efficiency and biocompatibility along with the less cell cytotoxicity of Ca2+-substituted MgFe2O4 nanoparticles were obsd. These outcomes propose that MgFe2O4 nanoparticles doped with Ca2+ ions are appropriate for biomedical applications, esp. for MHT cancer therapy.
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      Kossatz, S.; Grandke, J.; Couleaud, P.; Latorre, A.; Aires, A.; Crosbie-Staunton, K.; Ludwig, R.; Dähring, H.; Ettelt, V.; Lazaro-Carrillo, A.; Calero, M.; Sader, M.; Courty, J.; Volkov, Y.; Prina-Mello, A.; Villanueva, A.; Somoza, C.; Cortajarena, A. L.; Miranda, R.; Hilger, I. Efficient Treatment of Breast Cancer Xenografts with Multifunctionalized Iron Oxide Nanoparticles Combining Magnetic Hyperthermia and Anti-Cancer Drug Delivery. Breast Cancer Res. 2015, 17 (1), 66,  DOI: 10.1186/s13058-015-0576-1
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      Efficient treatment of breast cancer xenografts with multifunctionalized iron oxide nanoparticles combining magnetic hyperthermia and anti-cancer drug delivery
      Kossatz Susanne; Grandke Julia; Ludwig Robert; Dahring Heidi; Ettelt Volker; Hilger Ingrid; Couleaud Pierre; Latorre Alfonso; Aires Antonio; Calero Macarena; Villanueva Angeles; Somoza Alvaro; Cortajarena Aitziber L; Miranda Rodolfo; Couleaud Pierre; Latorre Alfonso; Aires Antonio; Somoza Alvaro; Cortajarena Aitziber L; Miranda Rodolfo; Crosbie-Staunton Kieran; Volkov Yuri; Prina-Mello Adriele; Lazaro-Carrillo Ana; Calero Macarena; Villanueva Angeles; Sader Maha; Courty Jose; Volkov Yuri; Prina-Mello Adriele
      Breast cancer research : BCR (2015), 17 (), 66 ISSN:.
      INTRODUCTION: Tumor cells can effectively be killed by heat, e.g. by using magnetic hyperthermia. The main challenge in the field, however, is the generation of therapeutic temperatures selectively in the whole tumor region. We aimed to improve magnetic hyperthermia of breast cancer by using innovative nanoparticles which display a high heating potential and are functionalized with a cell internalization and a chemotherapeutic agent to increase cell death. METHODS: The superparamagnetic iron oxide nanoparticles (MF66) were electrostatically functionalized with either Nucant multivalent pseudopeptide (N6L; MF66-N6L), doxorubicin (DOX; MF66-DOX) or both (MF66-N6LDOX). Their cytotoxic potential was assessed in a breast adenocarcinoma cell line MDA-MB-231. Therapeutic efficacy was analyzed on subcutaneous MDA-MB-231 tumor bearing female athymic nude mice. RESULTS: All nanoparticle variants showed an excellent heating potential around 500 W/g Fe in the alternating magnetic field (AMF, conditions: H=15.4 kA/m, f=435 kHz). We could show a gradual inter- and intracellular release of the ligands, and nanoparticle uptake in cells was increased by the N6L functionalization. MF66-DOX and MF66-N6LDOX in combination with hyperthermia were more cytotoxic to breast cancer cells than the respective free ligands. We observed a substantial tumor growth inhibition (to 40% of the initial tumor volume, complete tumor regression in many cases) after intratumoral injection of the nanoparticles in vivo. The proliferative activity of the remaining tumor tissue was distinctly reduced. CONCLUSION: The therapeutic effects of breast cancer magnetic hyperthermia could be strongly enhanced by the combination of MF66 functionalized with N6L and DOX and magnetic hyperthermia. Our approach combines two ways of tumor cell killing (magnetic hyperthermia and chemotherapy) and represents a straightforward strategy for translation into the clinical practice when injecting nanoparticles intratumorally.
      >> More from SciFinder ®
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      Beola, L.; Grazú, V.; Fernández-Afonso, Y.; Fratila, R. M.; De Las Heras, M.; De La Fuente, J. M.; Gutiérrez, L.; Asín, L. Critical Parameters to Improve Pancreatic Cancer Treatment Using Magnetic Hyperthermia: Field Conditions, Immune Response, and Particle Biodistribution. ACS Appl. Mater. Interfaces 2021, 13 (11), 12982– 12996,  DOI: 10.1021/acsami.1c02338
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      Critical Parameters to Improve Pancreatic Cancer Treatment Using Magnetic Hyperthermia: Field Conditions, Immune Response, and Particle Biodistribution
      Beola, Lilianne; Grazu, Valeria; Fernandez-Afonso, Yilian; Fratila, Raluca M.; de las Heras, Marcelo; de la Fuente, Jesus M.; Gutierrez, Lucia; Asin, Laura
      ACS Applied Materials & Interfaces (2021), 13 (11), 12982-12996CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
      Magnetic hyperthermia (MH) was used to treat a murine model of pancreatic cancer. This type of cancer is generally characterized by the presence of dense stroma that acts as a barrier for chemotherapeutic treatments. Several alternating magnetic field (AMF) conditions were evaluated using three-dimensional (3D) cell culture models loaded with magnetic nanoparticles (MNPs) to det. which conditions were producing a strong effect on the cell viability. Once the optimal AMF conditions were selected, in vivo expts. were carried out using similar frequency and field amplitude parameters. A marker of the immune response activation, calreticulin (CALR), was evaluated in cells from a xenograft tumor model after the MH treatment. Moreover, the distribution of nanoparticles within the tumor tissue was assessed by histol. anal. of tumor sections, observing that the exposure to the alternating magnetic field resulted in the migration of particles toward the inner parts of the tumor. Finally, a relationship between an inadequate body biodistribution of the particles after their intratumoral injection and a significant decrease in the effectiveness of the MH treatment was found. Animals in which most of the particles remained in the tumor area after injection showed higher redns. in the tumor vol. growth in comparison with those animals in which part of the particles were found also in the liver and spleen. Therefore, our results point out several factors that should be considered to improve the treatment effectiveness of pancreatic cancer by magnetic hyperthermia.
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      Chang, D.; Lim, M.; Goos, J. A. C. M.; Qiao, R.; Ng, Y. Y.; Mansfeld, F. M.; Jackson, M.; Davis, T. P.; Kavallaris, M. Biologically Targeted Magnetic Hyperthermia: Potential and Limitations. Front. Pharmacol. 2018, 9, 831,  DOI: 10.3389/fphar.2018.00831
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      Biologically targeted magnetic hyperthermia: potential and limitations
      Chang, David; Lim, May; Goos, Jeroen A. C. M.; Qiao, Ruirui; Ng, Yun Yee; Mansfeld, Friederike M.; Jackson, Michael; Davis, Thomas P.; Kavallaris, Maria
      Frontiers in Pharmacology (2018), 9 (), 831/1-831/20CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)
      Hyperthermia, the mild elevation of temp. to 40-43°C, can induce cancer cell death and enhance the effects of radiotherapy and chemotherapy. However, achievement of its full potential as a clin. relevant treatment modality has been restricted by its inability to effectively and preferentially heat malignant cells. The limited spatial resoln. may be circumvented by the i.v. administration of cancer-targeting magnetic nanoparticles that accumulate in the tumor, followed by the application of an alternating magnetic field to raise the temp. of the nanoparticles located in the tumor tissue. This targeted approach enables preferential heating of malignant cancer cells while sparing the surrounding normal tissue, potentially improving the effectiveness and safety of hyperthermia. Despite promising results in preclin. studies, there are numerous challenges that must be addressed before this technique can progress to the clinic. This review discusses these challenges and highlights the current understanding of targeted magnetic hyperthermia.
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      Laha, S. S.; Thorat, N. D.; Singh, G.; Sathish, C. I.; Yi, J.; Dixit, A.; Vinu, A. Rare-Earth Doped Iron Oxide Nanostructures for Cancer Theranostics: Magnetic Hyperthermia and Magnetic Resonance Imaging. Small 2022, 18 (11), 2104855,  DOI: 10.1002/smll.202104855
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      Rare-Earth Doped Iron Oxide Nanostructures for Cancer Theranostics: Magnetic Hyperthermia and Magnetic Resonance Imaging
      Laha, Suvra S.; Thorat, Nanasaheb D.; Singh, Gurwinder; Sathish, C. I.; Yi, Jiabao; Dixit, Ambesh; Vinu, Ajayan
      Small (2022), 18 (11), 2104855CODEN: SMALBC; ISSN:1613-6810. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Superparamagnetic iron oxide nanoparticles (SPIONs) have been extensively investigated during the last couple of decades because of their potential applications across various disciplines ranging from spintronics to nanotheranostics. However, pure iron oxide nanoparticles cannot meet the requirement for practical applications. Doping is considered as one of the most prominent and simplest techniques to achieve optimized multifunctional properties in nanomaterials. Doped iron oxides, particularly, rare-earth (RE) doped nanostructures have shown much-improved performance for a wide range of biomedical applications, including magnetic hyperthermia and magnetic resonance imaging (MRI), compared to pure iron oxide. Extensive investigations have revealed that bigger-sized RE ions possessing high magnetic moment and strong spin-orbit coupling can serve as promising dopants to significantly regulate the properties of iron oxides for advanced biomedical applications. This review provides a detailed investigation on the role of RE ions as primary dopants for engineering the structural and magnetic properties of Fe3O4 nanoparticles to carefully introspect and correlate their impact on cancer theranostics with a special focus on magnetic hyperthermia and MRI. In addn., prospects for achieving high-performance magnetic hyperthermia and MRI are thoroughly discussed. Finally, suggestions on future work in these two areas are also proposed.
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      Das, P.; Colombo, M.; Prosperi, D. Recent Advances in Magnetic Fluid Hyperthermia for Cancer Therapy. Colloids Surfaces B Biointerfaces 2019, 174, 42– 55,  DOI: 10.1016/j.colsurfb.2018.10.051
      9
      Recent advances in magnetic fluid hyperthermia for cancer therapy
      Das, Pradip; Colombo, Miriam; Prosperi, Davide
      Colloids and Surfaces, B: Biointerfaces (2019), 174 (), 42-55CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)
      Recently, magnetic fluid hyperthermia using biocompatible magnetic nanoparticles as heat mediators for cancer therapy has been extensively investigated due to its high efficiency and limited side effects. However, the development of more efficient heat nanomediators that exhibit very high specific absorption rate (SAR) value is essential for clin. application to overcome the several restrictions previously encountered due to the large quantity of nanomaterial required for effective treatment. In this review, we focus on the current progress in the development of magnetic nanoparticles based hyperthermia therapy as well as combined therapy harnessing hyperthermia with heat-mediated drug delivery for cancer treatment. We also address the fundamental principles of magnetic hyperthermia, basics of magnetism including the effect of several parameters on heating capacity, synthetic methods and nanoparticle surface chem. needed to design and develop an ideal magnetic nanoparticle heat mediator suitable for clin. translation in cancer therapy.
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    10. 10
      Caro, C.; Egea-Benavente, D.; Polvillo, R.; Royo, J. L.; Pernia Leal, M.; García-Martín, M. L. Comprehensive Toxicity Assessment of PEGylated Magnetic Nanoparticles for in Vivo Applications. Colloids Surfaces B Biointerfaces 2019, 177, 253– 259,  DOI: 10.1016/j.colsurfb.2019.01.051
      10
      Comprehensive Toxicity Assessment of PEGylated Magnetic Nanoparticles for in vivo applications
      Caro, Carlos; Egea-Benavente, David; Polvillo, Rocio; Royo, Jose Luis; Pernia Leal, Manuel; Garcia-Martin, Maria Luisa
      Colloids and Surfaces, B: Biointerfaces (2019), 177 (), 253-259CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)
      Magnetic nanoparticles (MNPs) represent one of the greatest promises for the development of a new generation of diagnostic agents for magnetic resonance imaging, with improved specificity and safety. Indeed, during the last decade the no. of studies published in this field has grown exponentially. However, the clin. translation achieved so far has been very limited. This situation is likely related to the fact that most studies are focused on the in vitro characterization of these new nanomaterials, and very few provide an exhaustive in vivo characterization, where key aspects, such as pharmacokinetics, bioavailability, and, most importantly, toxicity, are properly evaluated. In this work, we propose a protocol for the comprehensive assessment of the toxicity of MNPs, based on the use of zebrafish embryos as an intermediate screening step between cell culture assays and studies in rodents. MNPs with different cores, ferrite and manganese ferrite oxide, and sizes between 3 and 20 nm, were evaluated. Cell viability at a concn. of 50μg/mL of PEGylated MNPs was above 90% in all cases. However, the exposure of zebrafish embryos to manganese based MNPs at concns. above 100μg/mL showed a low survival rate (<50%). In contrast, no mortality (survival rate ∼100%) and normal hatching rate were obtained for the iron oxide MNPs. Based on these results, together with the physicochem. and magnetic properties (r2 = 153.6 mM-1s-1), the PEGylated 20 nm cubic shape iron oxide MNPs were selected and tested in mice, showing very good MRI contrast and, as expected, absence of toxicity.
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    11. 11
      Malhotra, N.; Lee, J.-S.; Liman, R. A. D.; Ruallo, J. M. S.; Villaflores, O. B.; Ger, T.-R.; Hsiao, C.-D. Potential Toxicity of Iron Oxide Magnetic Nanoparticles: A Review. Molecules 2020, 25 (14), 3159,  DOI: 10.3390/molecules25143159
      11
      Potential toxicity of iron oxide magnetic nanoparticles: a review
      Malhotra, Nemi; Lee, Jiann-Shing; Liman, Rhenz Alfred D.; Ruallo, Johnsy Margotte S.; Villaflores, Oliver B.; Ger, Tzong-Rong; Hsiao, Chung-Der
      Molecules (2020), 25 (14), 3159CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
      A review. The noteworthy intensification in the development of nanotechnol. has led to the development of various types of nanoparticles. The diverse applications of these nanoparticles make them desirable candidate for areas such as drug delivery, coasmetics, medicine, electronics, and contrast agents for magnetic resonance imaging (MRI) and so on. Iron oxide magnetic nanoparticles are a branch of nanoparticles which is specifically being considered as a contrast agent for MRI as well as targeted drug delivery vehicles, angiogenic therapy and chemotherapy as small size gives them advantage to travel intravascular or intracavity actively for drug delivery. Besides the mentioned advantages, the toxicity of the iron oxide magnetic nanoparticles is still less explored. For in vivo applications magnetic nanoparticles should be nontoxic and compatible with the body fluids. These particles tend to degrade in the body hence there is a need to understand the toxicity of the particles as whole and degraded products interacting within the body. Some nanoparticles have demonstrated toxic effects such inflammation, ulceration, and decreases in growth rate, decline in viability and triggering of neurobehavioral alterations in plants and cell lines as well as in animal models. The cause of nanoparticles' toxicity is attributed to their specific characteristics of great surface to vol. ratio, chem. compn., size, and dosage, retention in body, immunogenicity, organ specific toxicity, breakdown and elimination from the body. In the current review paper, we aim to sum up the current knowledge on the toxic effects of different magnetic nanoparticles on cell lines, marine organisms and rodents. We believe that the comprehensive data can provide significant study parameters and recent developments in the field. Thereafter, collecting profound knowledge on the background of the subject matter, will contribute to drive research in this field in a new sustainable direction.
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    12. 12
      Liu, X.; Zhang, Y.; Wang, Y.; Zhu, W.; Li, G.; Ma, X.; Zhang, Y.; Chen, S.; Tiwari, S.; Shi, K.; Zhang, S.; Fan, H. M.; Zhao, Y. X.; Liang, X. J. Comprehensive Understanding of Magnetic Hyperthermia for Improving Antitumor Therapeutic Efficacy. Theranostics 2020, 10 (8), 3793– 3815,  DOI: 10.7150/thno.40805
      12
      Comprehensive understanding of magnetic hyperthermia for improving antitumor therapeutic efficacy
      Liu, Xiaoli; Zhang, Yifan; Wang, Yanyun; Zhu, Wenjing; Li, Galong; Ma, Xiaowei; Zhang, Yihan; Chen, Shizhu; Tiwari, Shivani; Shi, Kejian; Zhang, Shouwen; Fan, Hai Ming; Zhao, Yong Xiang; Liang, Xing-Jie
      Theranostics (2020), 10 (8), 3793-3815CODEN: THERDS; ISSN:1838-7640. (Ivyspring International Publisher)
      A review. Magnetic hyperthermia (MH) has been introduced clin. as an alternative approach for the focal treatment of tumors. MH utilizes the heat generated by the magnetic nanoparticles (MNPs) when subjected to an alternating magnetic field (AMF). It has become an important topic in the nanomedical field due to their multitudes of advantages towards effective antitumor therapy such as high biosafety, deep tissue penetration, and targeted selective tumor killing. However, in order for MH to progress and to realize its paramount potential as an alternative choice for cancer treatment, tremendous challenges have to be overcome. Thus, the efficiency of MH therapy needs enhancement. In its recent 60-yr of history, the field of MH has focused primarily on heating using MNPs for therapeutic applications. Increasing the thermal conversion efficiency of MNPs is the fundamental strategy for improving therapeutic efficacy. Recently, emerging exptl. evidence indicates that MNPs-MH produces nano-scale heat effects without macroscopic temp. rise. A deep understanding of the effect of this localized induction heat for the destruction of subcellular/cellular structures further supports the efficacy of MH in improving therapeutic therapy. In this review, the currently available strategies for improving the antitumor therapeutic efficacy of MNPs-MH will be discussed. Firstly, the recent advancements in engineering MNP size, compn., shape, and surface to significantly improve their energy dissipation rates will be explored. Secondly, the latest studies depicting the effect of local induction heat for selectively disrupting cells/intracellular structures will be examd. Thirdly, strategies to enhance the therapeutics by combining MH therapy with chemotherapy, radiotherapy, immunotherapy, photothermal/photodynamic therapy (PDT), and gene therapy will be reviewed. Lastly, the prospect and significant challenges in MH-based antitumor therapy will be discussed. This review is to provide a comprehensive understanding of MH for improving antitumor therapeutic efficacy, which would be of utmost benefit towards guiding the users and for the future development of MNPs-MH towards successful application in medicine.
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    13. 13
      Erofeev, A.; Gorelkin, P.; Garanina, A.; Alova, A.; Efremova, M.; Vorobyeva, N.; Edwards, C.; Korchev, Y.; Majouga, A. Novel Method for Rapid Toxicity Screening of Magnetic Nanoparticles. Sci. Rep. 2018, 8 (1), 1– 11,  DOI: 10.1038/s41598-018-25852-4
      13
      Novel method for rapid toxicity screening of magnetic nanoparticles
      Erofeev, A.; Gorelkin, P.; Garanina, A.; Alova, A.; Efremova, M.; Vorobyeva, N.; Edwards, C.; Korchev, Y.; Majouga, A.
      Scientific Reports (2018), 8 (1), 1-11CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
      Iron oxide nanoparticles have attracted a great deal of research interest and have been widely used in bioscience and clin. research including as contrast agents for magnetic resonance imaging, hyperthermia and magnetic field assisted radionuclide therapy. It is therefore important to develop methods, which can provide high-throughput screening of biol. responses that can predict toxicity. The use of nanoelectrodes for single cell anal. can play a vital role in this process by providing relatively fast, comprehensive, and cost-effective assessment of cellular responses. We have developed a new method for in vitro study of the toxicity of magnetic nanoparticles (NP) based on the measurement of intracellular reactive oxygen species (ROS) by a novel nanoelectrode. Previous studies have suggested that ROS generation is frequently obsd. with NP toxicity. We have developed a stable probe for measuring intracellular ROS using platinized carbon nanoelectrodes with a cavity on the tip integrated into a micromanipulator on an upright microscope. Our results show a significant difference for intracellular levels of ROS measured in HEK293 and LNCaP cancer cells before and after exposure to 10 nm size iron oxide NP. These results are markedly different from ROS measured after cell incubation with the same concn. of NP using std. methods where no differences have been detected. In summary we have developed a label-free method for assessing nanoparticle toxicity using the rapid (less than 30 min) measurement of ROS with a novel nanoelectrode.
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    14. 14
      Setia, A.; Mehata, A. K.; Vikas; Malik, A. K.; Viswanadh, M. K.; Muthu, M. S. Theranostic Magnetic Nanoparticles: Synthesis, Properties, Toxicity, and Emerging Trends for Biomedical Applications. J. Drug Delivery Sci. Technol. 2023, 81, 104295,  DOI: 10.1016/j.jddst.2023.104295
      14
      Theranostic magnetic nanoparticles: Synthesis, properties, toxicity, and emerging trends for biomedical applications
      Setia, Aseem; Mehata, Abhishesh Kumar; Vikas; Malik, Ankit Kumar; Viswanadh, Matte Kasi; Muthu, Madaswamy S.
      Journal of Drug Delivery Science and Technology (2023), 81 (), 104295CODEN: JDDSAL; ISSN:1773-2247. (Elsevier B.V.)
      A review. Nanotechnol. provides a wide range of nanosized devices, termed as nanotheranostics, that are integrated with diagnostic and therapeutic properties for real-time monitoring and treatment of diseases. In order to diagnose and cure diseases at the cellular and mol. level, the theranostic nanomedicine must first be able to circulate throughout the body without being destroyed by the host's immune system. Further, this can be linked to a biol. ligand for targeting a specific organ or tissue. Novel non-invasive diagnostic agents, such as magnetic nanoparticles (MNPs), are currently employed in magnetic resonance imaging (MRI). Previously, they have been used for imaging various diseases; but new developments have unlocked the way for targeting the drug to the cellular membrane and multi-modal imaging with MNPs. For the prodn. of MNPs, a wide range of synthetic methods such as phys. and thermal degrdn., hydrothermal prodn., microemulsion, co-pptn., and polyol processes have been used, which include few examples of biosynthetic techniques. One of the biggest concern with MNPs is that they have potential toxicity issues in biomedical applications. Due to their reactive surface features and their capacity to penetrate the cell and tissue membranes, MNPs can elicit a powerful cytotoxic effect and hyperthermia. Numerous labs. have studied in vitro cellular toxicity of MNPs in a wide variety of cancer and normal cell lines, and their findings established the fact that at low concns., MNPs are nontoxic, and at high concns., they have marginal toxicity, demonstrating their biocompatibility and acceptable safety profile. Diagnostic imaging using nanosystems can be performed using the aforementioned approaches, including MRI, optical imaging, nuclear imaging, computed tomog., ultrasound etc. In this article, various theranostic magnetic nanosystems are discussed in the context of their manufg. and development for therapeutic and diagnostic use, focusing mainly on in vitro and in vivo applications. Further emphasis on their potential for integrating other nanostructures with current biotechnol., as well as the special qualities of magnetic nanosystems are further highlighted to explain the future role of magnetic nanosystems in the successful therapy.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXktVejsrs%253D&md5=877a1a4fc7c7b24a2c5e32e0c2811f2a
    15. 15
      Liu, X.; Zhang, Y.; Wang, Y.; Zhu, W.; Li, G.; Ma, X.; Zhang, Y.; Chen, S.; Tiwari, S.; Shi, K.; Zhang, S.; Fan, H. M.; Zhao, Y. X.; Liang, X. J. Comprehensive Understanding of Magnetic Hyperthermia for Improving Antitumor Therapeutic Efficacy. Theranostics 2020, 10 (8), 3793– 3815,  DOI: 10.7150/thno.40805
      15
      Comprehensive understanding of magnetic hyperthermia for improving antitumor therapeutic efficacy
      Liu, Xiaoli; Zhang, Yifan; Wang, Yanyun; Zhu, Wenjing; Li, Galong; Ma, Xiaowei; Zhang, Yihan; Chen, Shizhu; Tiwari, Shivani; Shi, Kejian; Zhang, Shouwen; Fan, Hai Ming; Zhao, Yong Xiang; Liang, Xing-Jie
      Theranostics (2020), 10 (8), 3793-3815CODEN: THERDS; ISSN:1838-7640. (Ivyspring International Publisher)
      A review. Magnetic hyperthermia (MH) has been introduced clin. as an alternative approach for the focal treatment of tumors. MH utilizes the heat generated by the magnetic nanoparticles (MNPs) when subjected to an alternating magnetic field (AMF). It has become an important topic in the nanomedical field due to their multitudes of advantages towards effective antitumor therapy such as high biosafety, deep tissue penetration, and targeted selective tumor killing. However, in order for MH to progress and to realize its paramount potential as an alternative choice for cancer treatment, tremendous challenges have to be overcome. Thus, the efficiency of MH therapy needs enhancement. In its recent 60-yr of history, the field of MH has focused primarily on heating using MNPs for therapeutic applications. Increasing the thermal conversion efficiency of MNPs is the fundamental strategy for improving therapeutic efficacy. Recently, emerging exptl. evidence indicates that MNPs-MH produces nano-scale heat effects without macroscopic temp. rise. A deep understanding of the effect of this localized induction heat for the destruction of subcellular/cellular structures further supports the efficacy of MH in improving therapeutic therapy. In this review, the currently available strategies for improving the antitumor therapeutic efficacy of MNPs-MH will be discussed. Firstly, the recent advancements in engineering MNP size, compn., shape, and surface to significantly improve their energy dissipation rates will be explored. Secondly, the latest studies depicting the effect of local induction heat for selectively disrupting cells/intracellular structures will be examd. Thirdly, strategies to enhance the therapeutics by combining MH therapy with chemotherapy, radiotherapy, immunotherapy, photothermal/photodynamic therapy (PDT), and gene therapy will be reviewed. Lastly, the prospect and significant challenges in MH-based antitumor therapy will be discussed. This review is to provide a comprehensive understanding of MH for improving antitumor therapeutic efficacy, which would be of utmost benefit towards guiding the users and for the future development of MNPs-MH towards successful application in medicine.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsl2mt73I&md5=ed815493184458ed7fe8fb6636e181ef
    16. 16
      Walter, A.; Billotey, C.; Garofalo, A.; Ulhaq-Bouillet, C.; Lefevre, C.; Taleb, J.; Laurent, S.; Vander Elst, L.; Muller, R. N.; Lartigue, L.; Gazeau, F.; Felder-Flesch, D.; Begin-Colin, S. Mastering the Shape and Composition of Dendronized Iron Oxide Nanoparticles to Tailor Magnetic Resonance Imaging and Hyperthermia. Chem. Mater. 2014, 26 (18), 5252– 5264,  DOI: 10.1021/cm5019025
      16
      Mastering the Shape and Composition of Dendronized Iron Oxide Nanoparticles To Tailor Magnetic Resonance Imaging and Hyperthermia
      Walter, Aurelie; Billotey, Claire; Garofalo, Antonio; Ulhaq-Bouillet, Corinne; Lefevre, Christophe; Taleb, Jacqueline; Laurent, Sophie; Vander Elst, Luce; Muller, Robert N.; Lartigue, Lenaic; Gazeau, Florence; Felder-Flesch, Delphine; Begin-Colin, Sylvie
      Chemistry of Materials (2014), 26 (18), 5252-5264CODEN: CMATEX; ISSN:0897-4756. (American Chemical Society)
      The current challenge in the field of nanomedicine is the design of multifunctional nano-objects effective both for the diagnosis and treatment of diseases. Dendronized FeO1-x@Fe3-xO4 nanoparticles with spherical, cubic, and octopode shapes and oxidized Fe3-xO4 nanocubes were synthesized and structurally and magnetically characterized. Strong exchange bias properties are highlighted in core-shell nanoparticles (NPs) due to magnetic interactions between their antiferromagnetic core and ferrimagnetic shell. Both in vitro relaxivity measurements and NMR distribution profiles confirmed the very good in vitro magnetic resonance imaging (MRI) properties of core-shell and cubic shape NPs, esp. at low concn. This might be related to the supplementary anisotropy introduced by the exchange bias properties and the cubic shape. The high heating values of core-shell NPs and oxidized nanocubes at low concn. are attributed to dipolar interactions inducing different clustering states, as a function of concn. In vivo MRI studies have also evidenced a clustering effect at the injection point, depending on the concn., and confirmed the very good in vivo MRI properties of core-shell NPs and oxidized nanocubes in particular at low concn. These core-shell and cubic shape dendronized nano-objects are very suitable to combine MRI and hyperthermia properties at low injected doses.
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    17. 17
      Gavilán, H.; Simeonidis, K.; Myrovali, E.; Mazarío, E.; Chubykalo-Fesenko, O.; Chantrell, R.; Balcells, L.; Angelakeris, M.; Morales, M. P.; Serantes, D. How Size, Shape and Assembly of Magnetic Nanoparticles Give Rise to Different Hyperthermia Scenarios. Nanoscale 2021, 13 (37), 15631– 15646,  DOI: 10.1039/D1NR03484G
      17
      How size, shape and assembly of magnetic nanoparticles give rise to different hyperthermia scenarios
      Gavilan, H.; Simeonidis, K.; Myrovali, E.; Mazario, E.; Chubykalo-Fesenko, O.; Chantrell, R.; Balcells, Ll.; Angelakeris, M.; Morales, M. P.; Serantes, D.
      Nanoscale (2021), 13 (37), 15631-15646CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
      The use of magnetic nanoparticles (MNPs) to locally increase the temp. at the nanoscale under the remote application of alternating magnetic fields (magnetic particle hyperthermia, MHT) has become an important subject of nanomedicine multidisciplinary research, focusing among other topics on the optimization of the heating performance of MNPs and their assemblies under the effect of the magnetic field. We report exptl. data of heat released by MNPs using a wide range of anisometric shapes and their assemblies in different media. We outline a basic theor. investigation, which assists the interpretation of the exptl. data, including the effect of the size, shape and assembly of MNPs on the MNPs' hysteresis loops and the max. heat delivered. We report heat release data of anisometric MNPs, including nanodisks, spindles (elongated nanoparticles) and nanocubes, analyzing, for a given shape, the size dependence. We study the MNPs either acting as individuals or assembled through a magnetic-field-assisted method. Thus, the phys. geometrical arrangement of these anisometric particles, the magnetization switching and the heat release (by means of the detn. of the specific adsorption rate, SAR values) under the application of AC fields have been analyzed and compared in aq. suspensions and after immobilization in agar matrix mimicking the tumor environment. The different nano-systems were analyzed when dispersed at random or in assembled configurations. We report a systematic fall in the SAR for all anisometric MNPs randomly embedded in a viscous environment. However, certain anisometric shapes will have a less marked, an almost total preservation or even an increase in SAR when embedded in a viscous environment with certain orientation, in contrast to the measurements in water soln. Discrepancies between theor. and exptl. values reflect the complexity of the systems due to the interplay of different factors such as size, shape and nanoparticle assembly due to magnetic interactions. We demonstrate that magnetic assembly holds great potential for producing materials with high functional and structural diversity, as we transform our nanoscale building blocks (anisometric MNPs) into a material displaying enhanced SAR properties.
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    18. 18
      Lee, J.-H.; Jang, J.; Choi, J.; Moon, S. H.; Noh, S.; Kim, J.; Kim, J.-G.; Kim, I.-S.; Park, K. I.; Cheon, J. Exchange-Coupled Magnetic Nanoparticles for Efficient Heat Induction. Nat. Nanotechnol. 2011, 6 (7), 418– 422,  DOI: 10.1038/nnano.2011.95
      18
      Exchange-coupled magnetic nanoparticles for efficient heat induction
      Lee, Jae-Hyun; Jang, Jung-tak; Choi, Jin-sil; Moon, Seung Ho; Noh, Seung-hyun; Kim, Ji-wook; Kim, Jin-Gyu; Kim, Il-Sun; Park, Kook In; Cheon, Jinwoo
      Nature Nanotechnology (2011), 6 (7), 418-422CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)
      The conversion of electromagnetic energy into heat by nanoparticles has the potential to be a powerful, non-invasive technique for biotechnol. applications such as drug release, disease treatment and remote control of single cell functions, but poor conversion efficiencies have hindered practical applications so far. In this Letter, we demonstrate a significant increase in the efficiency of magnetic thermal induction by nanoparticles. We take advantage of the exchange coupling between a magnetically hard core and magnetically soft shell to tune the magnetic properties of the nanoparticle and maximize the specific loss power, which is a gauge of the conversion efficiency. The optimized core-shell magnetic nanoparticles have specific loss power values that are an order of magnitude larger than conventional iron-oxide nanoparticles. We also perform an antitumor study in mice, and find that the therapeutic efficacy of these nanoparticles is superior to that of a common anticancer drug.
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    19. 19
      Jun, Y. W.; Seo, J. W.; Cheon, J. Nanoscaling Laws of Magnetic Nanoparticles and Their Applicabilities in Biomedical Sciences. Acc. Chem. Res. 2008, 41 (2), 179– 189,  DOI: 10.1021/ar700121f
      19
      Nanoscaling Laws of Magnetic Nanoparticles and Their Applicabilities in Biomedical Sciences
      Jun, Young-wook; Seo, Jung-wook; Cheon, Jinwoo
      Accounts of Chemical Research (2008), 41 (2), 179-189CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
      A review. Magnetic nanoparticles, which exhibit a variety of unique magnetic phenomena that are drastically different from those of their bulk counterparts, are garnering significant interest since these properties can be advantageous for utilization in a variety of applications ranging from storage media for magnetic memory devices to probes and vectors in the biomedical sciences. In this Account, the authors discuss the nanoscaling laws of magnetic nanoparticles including metals, metal ferrites, and metal alloys, while focusing on their size, shape, and compn. effects. Their fundamental magnetic properties such as blocking temp. (Tb), spin life time (τ), coercivity (Hc), and susceptibility (χ) are strongly influenced by the nanoscaling laws, and as a result, these scaling relationships can be leveraged to control magnetism from the ferromagnetic to the superparamagnetic regimes. At the same time, they can be used to tune magnetic values including Hc, χ, and remanence (Mr). For example, life time of magnetic spin is directly related to the magnetic anisotropy energy (KuV) and also the size and vol. of nanoparticles. The blocking temp. (Tb) changes from room temp. to 10 K as the size of cobalt nanoparticles is reduced from 13 to 2 nm. Similarly, Hc is highly susceptible to the anisotropy of nanoparticles, while satn. magnetization is directly related to the canting effects of the disordered surface magnetic spins and follows a linear relation upon plotting of ms1/3 vs. r-1. Therefore, the nanoscaling laws of magnetic nanoparticles are important not only for understanding the behavior of existing materials but also for developing novel nanomaterials with superior properties. Since magnetic nanoparticles can be easily conjugated with biol. important constituents such as DNA, peptides, and antibodies, it is possible to construct versatile nano-bio hybrid particles, which simultaneously possess magnetic and biol. functions for biomedical diagnostics and therapeutics. As demonstrated in this Account, nanoscaling laws for magnetic components are crit. to the design of optimized magnetic characteristics of hybrid nanoparticles and their enhanced applicability in the biomedical sciences including their utilizations as contrast enhancement agents for magnetic resonance imaging (MRI), ferromagnetic components for nano-bio hybrid structures, and translational vectors for magnetophoretic sensing of biol. species. In particular, systematic modulation of satn. magnetization of nanoparticle probes is important to maximize MR contrast effects and magnetic sepn. of biol. targets.
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    20. 20
      Mai, B. T.; Balakrishnan, P. B.; Barthel, M. J.; Piccardi, F.; Niculaes, D.; Marinaro, F.; Fernandes, S.; Curcio, A.; Kakwere, H.; Autret, G.; Cingolani, R.; Gazeau, F.; Pellegrino, T. Thermoresponsive Iron Oxide Nanocubes for an Effective Clinical Translation of Magnetic Hyperthermia and Heat-Mediated Chemotherapy. ACS Appl. Mater. Interfaces 2019, 11 (6), 5727– 5739,  DOI: 10.1021/acsami.8b16226
      20
      Thermoresponsive Iron Oxide Nanocubes for an Effective Clinical Translation of Magnetic Hyperthermia and Heat-Mediated Chemotherapy
      Mai Binh T; Balakrishnan Preethi B; Barthel Markus J; Piccardi Federica; Niculaes Dina; Marinaro Federica; Fernandes Soraia; Curcio Alberto; Kakwere Hamilton; Cingolani Roberto; Pellegrino Teresa; Mai Binh T; Balakrishnan Preethi B; Niculaes Dina; Autret Gwennhael; Gazeau Florence
      ACS applied materials & interfaces (2019), 11 (6), 5727-5739 ISSN:.
      The use of magnetic nanoparticles in oncothermia has been investigated for decades, but an effective combination of magnetic nanoparticles and localized chemotherapy under clinical magnetic hyperthermia (MH) conditions calls for novel platforms. In this study, we have engineered magnetic thermoresponsive iron oxide nanocubes (TR-cubes) to merge MH treatment with heat-mediated drug delivery, having in mind the clinical translation of the nanoplatform. We have chosen iron oxide based nanoparticles with a cubic shape because of their outstanding heat performance under MH clinical conditions, which makes them benchmark agents for MH. Accomplishing a surface-initiated polymerization of strongly interactive nanoparticles such as our iron oxide nanocubes, however, remains the main challenge to overcome. Here, we demonstrate that it is possible to accelerate the growth of a polymer shell on each nanocube by simple irradiation of a copper-mediated polymerization with a ultraviolet light (UV) light, which both speeds up the polymerization and prevents nanocube aggregation. Moreover, we demonstrate herein that these TR-cubes can carry chemotherapeutic doxorubicin (DOXO-loaded-TR-cubes) without compromising their thermoresponsiveness both in vitro and in vivo. In vivo efficacy studies showed complete tumor suppression and the highest survival rate for animals that had been treated with DOXO-loaded-TR-cubes, only when they were exposed to MH. The biodistribution of intravenously injected TR-cubes showed signs of renal clearance within 1 week and complete clearance after 5 months. This biomedical platform works under clinical MH conditions and at a low iron dosage, which will enable the translation of dual MH/heat-mediated chemotherapy, thus overcoming the clinical limitation of MH: i.e., being able to monitor tumor progression post-MH-treatment by magnetic resonance imaging (MRI).
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    21. 21
      Hammad, M.; Nica, V.; Hempelmann, R. Synthesis and Characterization of Bi-Magnetic Core/Shell Nanoparticles for Hyperthermia Applications. IEEE Trans. Magn. 2017, 53 (4), 1,  DOI: 10.1109/TMAG.2016.2635696
      There is no corresponding record for this reference.
    22. 22
      Hammad, M.; Nica, V.; Hempelmann, R. On-Off Switch-Controlled Doxorubicin Release from Thermo- and PH-Responsive Coated Bimagnetic Nanocarriers. J.Nanopart. Res. 2016, 18 (8), 234,  DOI: 10.1007/s11051-016-3550-7
      There is no corresponding record for this reference.
    23. 23
      Hammad, M.; Nica, V.; Hempelmann, R. On-Command Controlled Drug Release by Diels-Alder Reaction Using Bi-Magnetic Core/Shell Nano-Carriers. Colloids Surfaces B Biointerfaces 2017, 150, 15– 22,  DOI: 10.1016/j.colsurfb.2016.11.005
      23
      On-command controlled drug release by Diels-Alder reaction using Bi-magnetic core/shell nano-carriers
      Hammad, Mohaned; Nica, Valentin; Hempelmann, Rolf
      Colloids and Surfaces, B: Biointerfaces (2017), 150 (), 15-22CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)
      A novel bi-functional thermo-responsive system, consisting of core/shell bi-magnetic nanoparticles with furan surface functionality, is bonded with N-(2-Carboxyethyl)maleimide through Diels-Alder reaction. The chemotherapeutics doxorubicin is attached onto the surface, with a high loading efficiency of 92%. This system with high responsiveness to a high frequency external alternating magnetic field shows a very good therapeutic efficiency in hyperthermia and drug release at relatively low temps. (50°C). Polyhedron-shaped bi-magnetic nanoparticles ([email protected]) exhibit a significant increase of the specific energy absorption rate up to 455 W/g compared with the core nanoparticles (200 W/g). Real-time florescence spectroscopy studies demonstrate rapid release of doxorubicin up to 50% in 5 min and up to 92% after 15 min upon exposure to high frequency external alternating magnetic field. The stability is evaluated for 8 wk in phosphate buffer saline with a doxorubicin payload of 85%. In vitro studies using std. MTT cell assays with HeLa and Hep G2 lines prove an excellent biocompatibility with about 90% of cell viability after 24 h of treatment within the highest concn. of functionalized magnetic nanoparticles (200μg/mL). The results indicate a controlled drug release mediated by thermo-responsive switching under applied alternating magnetic field.
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    24. 24
      Tapeinos, C.; Marino, A.; Battaglini, M.; Migliorin, S.; Brescia, R.; Scarpellini, A.; De Julián Fernández, C.; Prato, M.; Drago, F.; Ciofani, G. Stimuli-Responsive Lipid-Based Magnetic Nanovectors Increase Apoptosis in Glioblastoma Cells through Synergic Intracellular Hyperthermia and Chemotherapy. Nanoscale 2019, 11 (1), 72– 88,  DOI: 10.1039/C8NR05520C
      24
      Stimuli-responsive lipid-based magnetic nanovectors increase apoptosis in glioblastoma cells through synergic intracellular hyperthermia and chemotherapy
      Tapeinos, Christos; Marino, Attilio; Battaglini, Matteo; Migliorin, Simone; Brescia, Rosaria; Scarpellini, Alice; De Julian Fernandez, Cesar; Prato, Mirko; Drago, Filippo; Ciofani, Gianni
      Nanoscale (2019), 11 (1), 72-88CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
      In this study, taking into consideration the limitations of current treatments of glioblastoma multiforme, we fabricated a biomimetic lipid-based magnetic nanovector with a good loading capacity and a sustained release profile of the encapsulated chemotherapeutic drug, temozolomide. In addn., these nanovectors presented excellent specific absorption rate values (up to 1345 W g-1) considering the size of the magnetic component, rendering them suitable as potential hyperthermia agents. The presented nanovectors were progressively internalized in U-87 MG cells and in their acidic compartments (i.e., lysosomes and late endosomes) without affecting the viability of the cells, and their ability to cross the blood-brain barrier was preliminarily investigated using an in vitro brain endothelial cell-model. When stimulated with alternating magnetic fields (20 mT, 750 kHz), the nanovectors demonstrated their ability to induce mild hyperthermia (43°C) and strong anticancer effects against U-87 MG cells (scarce survival of cells characterized by low proliferation rates and high apoptosis levels). The optimal anticancer effects resulted from the synergic combination of hyperthermia chronic stimulation and the controlled temozolomide release, highlighting the potential of the proposed drug-loaded lipid magnetic nanovectors for treatment of glioblastoma multiforme.
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    25. 25
      Gavrilov-Isaac, V.; Neveu, S.; Dupuis, V.; Taverna, D.; Gloter, A.; Cabuil, V. Synthesis of Trimagnetic Multishell MnFe2O4@CoFe2O4@NiFe2O4 Nanoparticles. Small 2015, 11 (22), 2614– 2618,  DOI: 10.1002/smll.201402845
      25
      Synthesis of Trimagnetic Multishell MnFe2O4@CoFe2O4@NiFe2O4 Nanoparticles
      Gavrilov-Isaac, Veronica; Neveu, Sophie; Dupuis, Vincent; Taverna, Dario; Gloter, Alexandre; Cabuil, Valerie
      Small (2015), 11 (22), 2614-2618CODEN: SMALBC; ISSN:1613-6810. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The authors report the synthesis and characterization of trimagnetic multishell MnFe2O4@CoFe2O4@NiFe2O4 nanoparticles with ferrite. These particles are a combination of a hard phase (CoFe2O4) and two soft phases (MnFe2O4 and NiFe2O4) and have unique magnetic characteristics. To synthesize MnFe2O4@CoFe2O4 core@shell and MnFe2O4@CoFe2O4@NiFe2O4 core@shell@shell nanoparticles, a seed-mediated growth at high temp. was used. The process and magnetic properties are described. The model is a good indication to predict the qual. modification of the coercive field when a new shell is added, but it needs to be improved in order to give quant. correct predictions. In particular, the quality of the interfaces between the different materials of the core and shells certainly plays an important role.
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    26. 26
      Nuñez, J. M.; Hettler, S.; Lima, E.; Goya, G. F.; Arenal, R.; Zysler, R. D.; Aguirre, M. H.; Winkler, E. L. Onion-like Fe3O4/MgO/CoFe2O4Magnetic Nanoparticles: New Ways to Control Magnetic Coupling between Soft and Hard Magnetic Phases. J. Mater. Chem. C 2022, 10 (41), 15339– 15352,  DOI: 10.1039/D2TC03144B
      26
      Onion-like Fe3O4/MgO/CoFe2O4 magnetic nanoparticles: new ways to control magnetic coupling between soft and hard magnetic phases
      Nunez, Jorge M.; Hettler, Simon; Lima Jr, Enio; Goya, Gerardo F.; Arenal, Raul; Zysler, Roberto D.; Aguirre, Myriam H.; Winkler, Elin L.
      Journal of Materials Chemistry C: Materials for Optical and Electronic Devices (2022), 10 (41), 15339-15352CODEN: JMCCCX; ISSN:2050-7534. (Royal Society of Chemistry)
      The control of magnetization inversion dynamics is one of the main challenges driving the design of new nanostructured magnetic materials for magnetoelectronic applications. Nanoparticles with an onion-like architecture offer a unique opportunity to expand the possibilities of combining different phases at the nanoscale and also modulating the coupling between magnetic phases by introducing spacers into the same structure. Here, we report the fabrication, by a three-step high temp. decompn. method, of Fe3O4/MgO/CoFe2O4 onion-like nanoparticles and their detailed structural anal., elemental compositional maps and magnetic response. The core/shell/shell nanoparticles present epitaxial growth and cubic shape with an overall size of (29 ± 6) nm. These nanoparticles consist of a cubic iron oxide core of 22 ± 4nm in size covered by two shells, the inner of magnesium oxide and the outer of cobalt ferrite of thicknesses 1 and 2.5 nm, resp. The magnetization measurements show a single reversion magnetization curve and the enhancement of the coercivity field, from HC 608 Oe for the Fe3O4/MgO to HC 5890 Oe for the Fe3O4/MgO/CoFe2O4 nanoparticles at T = 5 K, ascribed to the coupling between both ferrimagnetic phases with a coupling const. of JC= 2 erg cm-2. The system also exhibits an exchange bias effect, where the exchange bias field increases up to HEB 2850 Oe at 5 K accompanied by the broadening of the magnetization loop of HC 6650 Oe. This exchange bias effect originates from the freezing of the surface spins below the freezing temp. HF= 32 K that pinned the magnetic moment of the cobalt ferrite shell.
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    27. 27
      Grauer, O.; Jaber, M.; Hess, K.; Weckesser, M.; Schwindt, W.; Maring, S.; Wölfer, J.; Stummer, W. Combined Intracavitary Thermotherapy with Iron Oxide Nanoparticles and Radiotherapy as Local Treatment Modality in Recurrent Glioblastoma Patients. J. Neurooncol. 2019, 141 (1), 83– 94,  DOI: 10.1007/s11060-018-03005-x
      27
      Combined intracavitary thermotherapy with iron oxide nanoparticles and radiotherapy as local treatment modality in recurrent glioblastoma patients
      Grauer Oliver; Jaber Mohammed; Wolfer Johannes; Stummer Walter; Hess Katharina; Weckesser Matthias; Schwindt Wolfram; Maring Stephan; Wolfer Johannes
      Journal of neuro-oncology (2019), 141 (1), 83-94 ISSN:.
      BACKGROUND: There is an increasing interest in local tumor ablative treatment modalities that induce immunogenic cell death and the generation of antitumor immune responses. METHODS: We report six recurrent glioblastoma patients who were treated with intracavitary thermotherapy after coating the resection cavity wall with superparamagnetic iron oxide nanoparticles ("NanoPaste" technique). Patients underwent six 1-h hyperthermia sessions in an alternating magnetic field and, if possible, received concurrent fractionated radiotherapy at a dose of 39.6 Gy. RESULTS: There were no major side effects during active treatment. However, after 2-5 months, patients developed increasing clinical symptoms. CT scans showed tumor flare reactions with prominent edema around nanoparticle deposits. Patients were treated with dexamethasone and, if necessary, underwent re-surgery to remove nanoparticles. Histopathology revealed sustained necrosis directly adjacent to aggregated nanoparticles without evidence for tumor activity. Immunohistochemistry showed upregulation of Caspase-3 and heat shock protein 70, prominent infiltration of macrophages with ingested nanoparticles and CD3(+) T-cells. Flow cytometric analysis of freshly prepared tumor cell suspensions revealed increased intracellular ratios of IFN-γ to IL-4 in CD4(+) and CD8(+) memory T cells, and activation of tumor-associated myeloid cells and microglia with upregulation of HLA-DR and PD-L1. Two patients had long-lasting treatment responses > 23 months without receiving any further therapy. CONCLUSION: Intracavitary thermotherapy combined with radiotherapy can induce a prominent inflammatory reaction around the resection cavity which might trigger potent antitumor immune responses possibly leading to long-term stabilization of recurrent GBM patients. These results warrant further investigations in a prospective phase-I trial.
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    28. 28
      Park, Y.; Demessie, A. A.; Luo, A.; Taratula, O. R.; Moses, A. S.; Do, P.; Campos, L.; Jahangiri, Y.; Wyatt, C. R.; Albarqi, H. A.; Farsad, K.; Slayden, O. D.; Taratula, O. Targeted Nanoparticles with High Heating Efficiency for the Treatment of Endometriosis with Systemically Delivered Magnetic Hyperthermia. Small 2022, 18 (24), 1– 15,  DOI: 10.1002/smll.202107808
      There is no corresponding record for this reference.
    29. 29
      Guntnur, R. T.; Muzzio, N.; Gomez, A.; Macias, S.; Galindo, A.; Ponce, A.; Romero, G. On-Demand Chemomagnetic Modulation of Striatal Neurons Facilitated by Hybrid Magnetic Nanoparticles. Adv. Funct. Mater. 2022, 32, 2204732,  DOI: 10.1002/adfm.202204732
      29
      On-Demand Chemomagnetic Modulation of Striatal Neurons Facilitated by Hybrid Magnetic Nanoparticles
      Guntnur, Rohini Thevi; Muzzio, Nicolas; Gomez, Amanda; Macias, Sean; Galindo, Arturo; Ponce, Arturo; Romero, Gabriela
      Advanced Functional Materials (2022), 32 (35), 2204732CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Minimally invasive manipulation of cell signaling is crit. in basic neuroscience research and in developing therapies for neurol. disorders. Here, a wireless chemomagnetic neuromodulation platform for the on-demand control of primary striatal neurons that relies on nanoscale heating events is described. Iron oxide magnetic nanoparticles (MNPs) are functionally coated with thermoresponsive poly (oligo (ethylene glycol) Me ether methacrylate) (POEGMA) brushes loaded with dopamine. Dopamine loaded MNPs-POEGMA are co-cultured with primary striatal neurons. When alternating magnetic fields (AMF) are applied, MNPs undergo hysteresis power loss and dissipate heat. The local heat produced by MNPs initiates a thermodn. phase transition on POEGMA brushes resulting in polymer collapse and dopamine release. AMF-triggered dopamine release enhances the response of dopamine ion channels expressed on the cell membranes enhancing the activity ≈50% of striatal neurons subjected to the treatment. Chemomagnetic actuation on dopamine receptors is confirmed by blocking D1 and D2 receptors. The reversible thermodn. phase transition of POEGMA brushes allow the on-demand release of dopamine in multiple microdoses. AMF-triggered dopamine release from MNPs-POEGMA causes neither cell cytotoxicity nor promotes cell reactive oxygen species prodn. This research represents a fundamental step forward for the chemomagnetic control of neural activity using hybrid magnetic nanomaterials with tailored phys. properties.
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    30. 30
      Pucci, C.; Degl’Innocenti, A.; Belenli Gümüş, M.; Ciofani, G. Superparamagnetic Iron Oxide Nanoparticles for Magnetic Hyperthermia: Recent Advancements, Molecular Effects, and Future Directions in the Omics Era. Biomater. Sci. 2022, 10 (9), 2103– 2121,  DOI: 10.1039/D1BM01963E
      30
      Superparamagnetic iron oxide nanoparticles for magnetic hyperthermia: recent advancements, molecular effects, and future directions in the omics era
      Pucci, Carlotta; Degl'Innocenti, Andrea; Belenli Gumus, Melike; Ciofani, Gianni
      Biomaterials Science (2022), 10 (9), 2103-2121CODEN: BSICCH; ISSN:2047-4849. (Royal Society of Chemistry)
      A review. Superparamagnetic iron oxide nanoparticles (SPIONs) have attracted attention in the biomedical field thanks to their ability to prompt hyperthermia in response to an alternated magnetic field. Hyperthermia is well known for inducing cell death, in particular in tumor cells, which seem to have a higher sensitivity to temp. increases. For this reason, hyperthermia has been recommended as a therapeutic tool against cancer. Despite the potentialities of this approach, little is still known about the effects provoked by magnetic hyperthermia at the mol. level, and about the particular cell death mechanisms that are activated. Nevertheless, in-depth knowledge of this aspect would allow improvement of therapeutic outcomes and favor clin. translation. Moreover, in the last few decades, a lot of effort has been put into finding an effective delivery strategy that could improve SPION biodistribution and localisation at the action site. The aim of this review is to provide a general outline of magnetic hyperthermia, focusing on iron oxide nanoparticles and their interactions with magnetic fields, as well as on new strategies to efficiently deliver them to the target site, and on recent in vitro and in vivo studies proposing possible cell death pathways activated by the treatment. We will also cover their current clin. status, and discuss the contributions of omics in understanding mol. interactions between iron oxide nanoparticles and the biol. environment.
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    31. 31
      Pudlarz, A.; Szemraj, J. Nanoparticles as Carriers of Proteins, Peptides and Other Therapeutic Molecules. Open Life Sci. 2018, 13 (1), 285– 298,  DOI: 10.1515/biol-2018-0035
      31
      Nanoparticles as carriers of proteins, peptides and other therapeutic molecules
      Pudlarz, Agnieszka; Szemraj, Janusz
      Open Life Sciences (2018), 13 (1), 285-298CODEN: OLSPBT; ISSN:2391-5412. (De Gruyter Open Ltd.)
      Nanoparticles have many applications both in industry and medicine. Depending upon their phys. and chem. properties, they can be used as carriers of therapeutic mols. or as therapeutics. Nanoparticles are made of synthetic or natural polymers, lipids or metals. Their use allows for faster transport to the place of action, thus prolonging its presence in the body and limiting side effects. In addn., the use of such a drug delivery system protects the drug from rapid disintegration and elimination from the body. In recent years, the use of proteins and peptides as therapeutic mols. has grown significantly. Unfortunately, proteins are subject to enzymic digestion and can cause unwanted immune response beyond therapeutic action. The use of drug carriers can minimize undesirable side effects and reduce the dose of medication needed to achieve the therapeutic effect. The current study presents the use of several selected drug delivery systems for the delivery of proteins, peptides and other therapeutic mols.
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    32. 32
      Longoria-García, S.; Sánchez-Domínguez, C. N.; Gallardo-Blanco, H. Recent Applications of Cell-Penetrating Peptide Guidance of Nanosystems in Breast and Prostate Cancer (Review). Oncol. Lett. 2022, 23 (3), 103,  DOI: 10.3892/ol.2022.13223
      32
      Recent applications of cell-penetrating peptide guidance of nanosystems in breast and prostate cancer (review)
      Longoria-Garcia, Samuel; Sanchez-Dominguez, Celia Nohemi; Gallardo-Blanco, Hugo Leonid
      Oncology Letters (2022), 23 (3), 103CODEN: OLNEB5; ISSN:1792-1082. (Spandidos Publications Ltd.)
      Cell-penetrating peptides (CPPs) are small peptides from natural sources or designed from other protein sequences that can penetrate cell membranes. This property has been used in biomedicine to add them to biomols. to improve their capacity for cell internalization and as a guidance tool for specific cell types. CPPs have been shown to enhance cellular uptake in vitro and in vivo, improving the efficacy of anticancer drugs such as doxorubicin and paclitaxel, while also limiting their cytotoxic effects on healthy cells and tissues. The current study reviews the internalization and major therapeutic results achieved from the functionalization of nanosystems with CPPs for guidance into breast and prostate cancer cells in vitro and in vivo. In addn., the practical results obtained are specifically discussed for use as a starting point for scientists looking to begin research in this field.
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    33. 33
      Zhu, L.; Zhong, Y.; Wu, S.; Yan, M.; Cao, Y.; Mou, N.; Wang, G.; Sun, D.; Wu, W. Cell Membrane Camouflaged Biomimetic Nanoparticles: Focusing on Tumor Theranostics. Mater. Today Bio 2022, 14, 100228,  DOI: 10.1016/j.mtbio.2022.100228
      33
      Cell membrane camouflaged biomimetic nanoparticles: Focusing on tumor theranostics
      Zhu, Li; Zhong, Yuan; Wu, Shuai; Yan, Meng; Cao, Yu; Mou, Nianlian; Wang, Guixue; Sun, Da; Wu, Wei
      Materials Today Bio (2022), 14 (), 100228CODEN: MTBAC2; ISSN:2590-0064. (Elsevier Ltd.)
      Nanoparticles (NPs) modified by cell membranes represent an emerging biomimetic platform that can mimic the innate biol. functions resulting from the various cell membranes in biol. systems. researchers focus on constructing the cell membrane camouflaged NPs using a wide variety of cells, such as red blood cell membranes (RBC), macrophages and cancer cells. Cell membrane camouflaged NPs (CMNPs) inherit the compn. of cell membranes, including specific receptors, antigens, proteins, for target delivering to the tumor, escaping immune from clearance, and prolonging the blood circulation time, etc. Combining cell membrane-derived biol. functions and the NP cores acted cargo carriers to encapsulate the imaging agents, CMNPs are widely developed to apply in tumor imaging techniques, including computed tomog. (CT), magnetic resonance imaging (MRI), fluorescence imaging (FL) and photoacoustic imaging (PA). Herein, in this review, we systematically summarize the superior functions of various CMNPs in tumor imaging, esp. highlighting the advanced applications in different imaging techniques, which is to provide the theor. supports for the development of precise guided imaging and tumor treatment.
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    34. 34
      Rao, L.; Cai, B.; Bu, L. L.; Liao, Q. Q.; Guo, S. S.; Zhao, X. Z.; Dong, W. F.; Liu, W. Microfluidic Electroporation-Facilitated Synthesis of Erythrocyte Membrane-Coated Magnetic Nanoparticles for Enhanced Imaging-Guided Cancer Therapy. ACS Nano 2017, 11 (4), 3496– 3505,  DOI: 10.1021/acsnano.7b00133
      34
      Microfluidic Electroporation-Facilitated Synthesis of Erythrocyte Membrane-Coated Magnetic Nanoparticles for Enhanced Imaging-Guided Cancer Therapy
      Rao, Lang; Cai, Bo; Bu, Lin-Lin; Liao, Qing-Quan; Guo, Shi-Shang; Zhao, Xing-Zhong; Dong, Wen-Fei; Liu, Wei
      ACS Nano (2017), 11 (4), 3496-3505CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Biomimetic cell membrane-coated nanoparticles (CM-NPs) with superior biochem. properties have been broadly utilized for various biomedical applications. Currently, researchers primarily focus on using ultrasonic treatment and mech. extrusion to improve the synthesis of CM-NPs. In this work, we demonstrate that microfluidic electroporation can effectively facilitate the synthesis of CM-NPs. To test it, Fe3O4 magnetic nanoparticles (MNs) and red blood cell membrane-derived vesicles (RBC-vesicles) are infused into a microfluidic device. When the mixt. of MNs and RBC-vesicles flow through the electroporation zone, the elec. pulses can effectively promote the entry of MNs into RBC-vesicles. After that, the resulting RBC membrane-capped MNs (RBC-MNs) are collected from the chip and injected into exptl. animals to test the in vivo performance. Owing to the superior magnetic and photothermal properties of the MN cores and the long blood circulation characteristic of the RBC membrane shells, core-shell RBC-MNs were used for enhanced tumor magnetic resonance imaging (MRI) and photothermal therapy (PTT). Due to the completer cell membrane coating, RBC-MNs prepd. by microfluidic electroporation strategy exhibit significantly better treatment effect than the one fabricated by conventional extrusion. We believe the combination of microfluidic electroporation and CM-NPs provides an insight into the synthesis of bioinpired nanoparticles to improve cancer diagnosis and therapy.
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    35. 35
      Yu, G. T.; Rao, L.; Wu, H.; Yang, L. L.; Bu, L. L.; Deng, W. W.; Wu, L.; Nan, X.; Zhang, W. F.; Zhao, X. Z.; Liu, W.; Sun, Z. J. Myeloid-Derived Suppressor Cell Membrane-Coated Magnetic Nanoparticles for Cancer Theranostics by Inducing Macrophage Polarization and Synergizing Immunogenic Cell Death. Adv. Funct. Mater. 2018, 28 (37), 1801389,  DOI: 10.1002/adfm.201801389
      There is no corresponding record for this reference.
    36. 36
      Kondo, E.; Iioka, H.; Saito, K. Tumor-Homing Peptide and Its Utility for Advanced Cancer Medicine. Cancer Sci. 2021, 112 (6), 2118– 2125,  DOI: 10.1111/cas.14909
      36
      Tumor-homing peptide and its utility for advanced cancer medicine
      Kondo, Eisaku; Iioka, Hidekazu; Saito, Ken
      Cancer Science (2021), 112 (6), 2118-2125CODEN: CSACCM; ISSN:1349-7006. (Wiley-Blackwell)
      A review. Cell-penetrating peptides, such as antibodies, have gained great attention as tools for the development of specific delivery systems for payloads, which might be applied as non-invasive carriers in vivo. Among these, tumor-homing peptides recently have been studied for use in tumor medicine. Tumor-homing peptides are oligopeptides, usually consisting of 30 or fewer amino acids that are efficiently and specifically incorporated into tumor cells, suggesting their potential use in establishing novel non-invasive tumor imaging systems for diagnostic and therapeutic applications. Here, we briefly introduce the biol. characteristics of our tumor-homing peptides, focusing esp. on those developed using a random peptide library constructed using mRNA display technol. The advantage of the tumor-homing peptides is their biol. safety, given that these mols. do not show significant cytotoxicity against non-neoplastic cells; lack serious antigenicity, which alternatively might evoke unfavorable immune responses and inflammation in vivo; and are rapidly incorporated into target cells/tissues, with rates exceeding those seen for antibodies. Given their small size, tumor-homing peptides also are easy to modify and redesign. Based on these merits, tumor-homing peptides are expected to find wide application in various aspects of tumor medicine, including imaging diagnostics (eg, with dye-conjugated probes for direct visualization of invasive/metastatic tumor lesions in vivo) and therapeutics (eg, using peptide-drug conjugates [PDCs] for tumor targeting). Although further evidence will be required to demonstrate their practical utility, tumor-homing peptides are expected to show great potential as a next-generation bio-tool contributing to precision medicine for cancer patients.
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    37. 37
      Wada, A.; Terashima, T.; Kageyama, S.; Yoshida, T.; Narita, M.; Kawauchi, A.; Kojima, H. Efficient Prostate Cancer Therapy with Tissue-Specific Homing Peptides Identified by Advanced Phage Display Technology. Mol. Ther. - Oncolytics 2019, 12 (3), 138– 146,  DOI: 10.1016/j.omto.2019.01.001
      37
      Efficient Prostate Cancer Therapy with Tissue-Specific Homing Peptides Identified by Advanced Phage Display Technology
      Wada, Akinori; Terashima, Tomoya; Kageyama, Susumu; Yoshida, Tetsuya; Narita, Mitsuhiro; Kawauchi, Akihiro; Kojima, Hideto
      Molecular Therapy--Oncolytics (2019), 12 (), 138-146CODEN: MTOHDL; ISSN:2372-7705. (Elsevier)
      Selective targeting of drugs to tumor cells is a key goal in oncol. Here, we performed an in vivo phage display to identify peptides that specifically target xenografted prostate cancer cells. This yielded three peptide candidates, LN1 (C-TGTPARQ-C), LN2 (C-KNSMFAT-C), and LN3 (C-TNKHSPK-C); each of these peptides was synthesized and evaluated for binding and biol. activity. LN1 showed the highest avidity for LNCaP prostate cancer cells in vitro and was thus administered to tumor-bearing mice to evaluate in vivo binding. Strikingly, LN1 specifically bound to the tumor tissue and exhibited very low reactivity with normal liver and kidney tissues. To demonstrate that LN1 could specifically deliver drugs to prostate cancer tissue, a therapeutic peptide, LN1-KLA (C-TGTPARQ-C-GGG-D[KLAKLAK]2), was prepd. and used to treat LNCaP cells in vitro and was also administered to tumor-bearing mice. The therapeutic peptide significantly suppressed growth of the cells both in vitro and in vivo. Our study shows that a selective homing peptide strategy could facilitate cell-specific targeting of therapeutics while avoiding adverse reactions in normal tissues.
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    38. 38
      Wang, L.; Wang, X.; Luo, J.; Wanjala, B. N.; Wang, C.; Chernova, N. A.; Engelhard, M. H.; Liu, Y.; Bae, I. T.; Zhong, C. J. Core-Shell-Structured Magnetic Ternary Nanocubes. J. Am. Chem. Soc. 2010, 132 (50), 17686– 17689,  DOI: 10.1021/ja1091084
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      Core-Shell-Structured Magnetic Ternary Nanocubes
      Wang, Ling-Yan; Wang, Xin; Luo, Jin; Wanjala, Bridgid N.; Wang, Chong-Min; Chernova, Natasha A.; Engelhard, Mark H.; Liu, Yao; Bae, In-Tae; Zhong, Chuan-Jian
      Journal of the American Chemical Society (2010), 132 (50), 17686-17689CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The authors report a novel core-shell-structured ternary nanocube of MnZn ferrite synthesized by controlling the reaction temp. and compn. in the absence of conventionally used reducing agents. The highly monodispersed core-shell structure consists of an Fe3O4 core and an MnZn Ferrite shell. The observation of a Moire pattern indicates that the core and the shell are two highly cryst. materials with slightly different lattice consts. that are rotated relative to each other by a small angle. The ternary core-shell nanocubes display magnetic properties regulated by a combination of the core-shell compn. and exhibit an increased coercivity and field-cooled/zero-field-cooled characteristics drastically different from those of regular MnZn ferrite nanoparticles. The ability to engineer the spatial nanostructures of ternary magnetic nanoparticles in terms of shape and compn. offers at.-level versatility in fine-tuning the nanoscale magnetic properties.
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    39. 39
      Tong, S.; Hou, S.; Ren, B.; Zheng, Z.; Bao, G. Self-Assembly of Phospholipid-PEG Coating on Nanoparticles through Dual Solvent Exchange. Nano Lett. 2011, 11 (9), 3720– 3726,  DOI: 10.1021/nl201978c
      39
      Self-Assembly of Phospholipid-PEG Coating on Nanoparticles through Dual Solvent Exchange
      Tong, Sheng; Hou, Si-Jian; Ren, Bin-Bin; Zheng, Zhi-Lan; Bao, Gang
      Nano Letters (2011), 11 (9), 3720-3726CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
      We coated nanoparticles including iron oxide nanoparticles and quantum dots with phospholipid-PEG using the newly developed dual solvent exchange method and demonstrated that, compared with the conventional film hydration method, the coating efficiency and quality of coated nanoparticles can be significantly improved. A better control of surface coating d. and the amt. of reactive groups on nanoparticle surface is achieved, allowing conjugation of different moieties with desirable surface concns., thus facilitating biomedical applications of nanoparticles.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpsFOntr0%253D&md5=2d34dd827271b918697c004f8b21cc5d
    40. 40
      De Pasquale, D.; Marino, A.; Tapeinos, C.; Pucci, C.; Rocchiccioli, S.; Michelucci, E.; Finamore, F.; McDonnell, L.; Scarpellini, A.; Lauciello, S.; Prato, M.; Larrañaga, A.; Drago, F.; Ciofani, G. Homotypic Targeting and Drug Delivery in Glioblastoma Cells through Cell Membrane-Coated Boron Nitride Nanotubes. Mater. Des. 2020, 192, 108742,  DOI: 10.1016/j.matdes.2020.108742
      40
      Homotypic targeting and drug delivery in glioblastoma cells through cell membrane-coated boron nitride nanotubes
      De Pasquale, Daniele; Marino, Attilio; Tapeinos, Christos; Pucci, Carlotta; Rocchiccioli, Silvia; Michelucci, Elena; Finamore, Francesco; McDonnell, Liam; Scarpellini, Alice; Lauciello, Simone; Prato, Mirko; Larranaga, Aitor; Drago, Filippo; Ciofani, Gianni
      Materials & Design (2020), 192 (), 108742CODEN: MADSD2; ISSN:0264-1275. (Elsevier Ltd.)
      Glioblastoma multiforme (GBM) is one of the most aggressive types of brain cancer, characterized by rapid progression, resistance to treatments, and low survival rates; the development of a targeted treatment for this disease is still today an unattained objective. Among the different strategies developed in the latest few years for the targeted delivery of nanotherapeutics, homotypic membrane-membrane recognition is one of the most promising and efficient. In this work, we present an innovative drug-loaded nanocarrier with improved targeting properties based on the homotypic recognition of GBM cells. The developed nanoplatform consists of boron nitride nanotubes (BNNTs) loaded with doxorubicin (Dox) and coated with cell membranes (CM) extd. from GBM cells (Dox-CM-BNNTs). We demonstrated as Dox-CM-BNNTs are able to specifically target and kill GBM cells in vitro, leaving unaffected healthy brain cells, upon successful crossing an in vitro blood-brain barrier model. The excellent targeting performances of the nanoplatform can be ascribed to the protein component of the membrane coating, and proteomic anal. of differently expressed membrane proteins present on the CM of GBM cells and of healthy astrocytes allowed the identification of potential candidates involved in the process of homotypic cancer cell recognition.
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    41. 41
      Pucci, C.; De Pasquale, D.; Marino, A.; Martinelli, C.; Lauciello, S.; Ciofani, G. Hybrid Magnetic Nanovectors Promote Selective Glioblastoma Cell Death through a Combined Effect of Lysosomal Membrane Permeabilization and Chemotherapy. ACS Appl. Mater. Interfaces 2020, 12 (26), 29037– 29055,  DOI: 10.1021/acsami.0c05556
      41
      Hybrid Magnetic Nanovectors Promote Selective Glioblastoma Cell Death through a Combined Effect of Lysosomal Membrane Permeabilization and Chemotherapy
      Pucci, Carlotta; De Pasquale, Daniele; Marino, Attilio; Martinelli, Chiara; Lauciello, Simone; Ciofani, Gianni
      ACS Applied Materials & Interfaces (2020), 12 (26), 29037-29055CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
      Glioblastoma multiforme is the most aggressive brain tumor, due to its high invasiveness and genetic heterogeneity. Moreover, the blood-brain barrier prevents many drugs from reaching a therapeutic concn. at the tumor site, and most of the chemotherapeutics lack in specificity toward cancer cells, accumulating in both healthy and diseased tissues, with severe side effects. Here, we present in vitro investigations on lipid-based nanovectors encapsulating a drug, nutlin-3a, and superparamagnetic iron oxide nanoparticles, to combine the proapoptotic action of the drug and the hyperthermia mediated by superparamagnetic iron oxide nanoparticles stimulated with an alternating magnetic field. The nanovectors are functionalized with the peptide angiopep-2 to induce receptor-mediated transcytosis through the blood-brain barrier and to target a receptor overexpressed by glioma cells. The glioblastoma multiforme targeting efficiency and the blood-brain barrier crossing abilities were tested through in vitro fluidic models, where different human cell lines were placed to mimic the tumor microenvironment. These nanovectors successfully cross the blood-brain barrier model, maintaining their targeting abilities for glioblastoma multiforme with minimal interaction with healthy cells. Moreover, we showed that nanovector-assisted hyperthermia induces a lysosomal membrane permeabilization that not only initiates a caspase-dependent apoptotic pathway, but also enhances the anticancer efficacy of the drug.
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    42. 42
      Rasband, W. S. ImageJ; US National Institutes of Health: Bethesda, Maryland, USA, 1997–2018. https://imagej.nih.gov/ij/.
      There is no corresponding record for this reference.
    43. 43
      Fairley, N.; Fernandez, V.; Richard-Plouet, M.; Guillot-Deudon, C.; Walton, J.; Smith, E.; Flahaut, D.; Greiner, M.; Biesinger, M.; Tougaard, S.; Morgan, D.; Baltrusaitis, J. Systematic and Collaborative Approach to Problem Solving Using X-Ray Photoelectron Spectroscopy. Appl. Surf. Sci. Adv. 2021, 5 (March), 100112,  DOI: 10.1016/j.apsadv.2021.100112
      There is no corresponding record for this reference.
    44. 44
      https://www.malvernpanalytical.com/en/about-us/our-brands/panalytical.
      There is no corresponding record for this reference.
    45. 45
      Fang, C.; Veiseh, O.; Kievit, F.; Bhattarai, N.; Wang, F.; Stephen, Z.; Li, C.; Lee, D.; Ellenbogen, R. G.; Zhang, M. Functionalization of Iron Oxide Magnetic Nanoparticles with Targeting Ligands: Their Physicochemical Properties and in Vivo Behavior. Nanomedicine 2010, 5 (9), 1357– 1369,  DOI: 10.2217/nnm.10.55
      45
      Functionalization of iron oxide magnetic nanoparticles with targeting ligands: their physicochemical properties and in vivo behavior
      Fang, Chen; Veiseh, Omid; Kievit, Forrest; Bhattarai, Narayan; Wang, Freddy; Stephen, Zach; Li, Chun; Lee, Donghoon; Ellenbogen, Richard G.; Zhang, Miqin
      Nanomedicine (London, United Kingdom) (2010), 5 (9), 1357-1369CODEN: NLUKAC; ISSN:1743-5889. (Future Medicine Ltd.)
      Aim: To develop and evaluate two tumor-specific nanoprobes by functionalization of a polyethylene glycol-immobilized nanoparticle with arginine-glycine-aspartic acid (RGD) or chlorotoxin ligand that targets αvβ3 integrin and matrix metalloproteinase-2 receptors, resp. Materials & methods: The nanoprobes were made of iron oxide cores, biocompatible polymer coating, and surface-conjugated RGD or chlorotoxin peptide. The tumor-targeting specificity of the nanoprobes was evaluated both in vitro and in vivo. Results & discussion: Both nanoprobes were highly dispersive and exhibited excellent long-term stability in cell culture media. The RGD-conjugated nanoprobe displayed a strong initial accumulation near neovasculatures in tumors followed by quick clearance. Conversely, the chlorotoxin-enabled nanoprobe exhibited sustained accumulation throughout the tumor. Conclusion: These findings revealed the influence of the targeting ligands on the intratumoral distribution of the ligand-enabled nanoprobes. With flexible surface chem., our nanoparticle platform can be used in a modular fashion to conjugate biomols. for intended applications.
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    46. 46
      Shi, W.; Cao, X.; Liu, Q.; Zhu, Q.; Liu, K.; Deng, T.; Yu, Q.; Deng, W.; Yu, J.; Wang, Q.; Xu, X. Hybrid Membrane-Derived Nanoparticles for Isoliquiritin Enhanced Glioma Therapy. Pharmaceuticals 2022, 15 (9), 1059,  DOI: 10.3390/ph15091059
      46
      Hybrid Membrane-Derived Nanoparticles for Isoliquiritin Enhanced Glioma Therapy
      Shi, Wenwan; Cao, Xia; Liu, Qi; Zhu, Qin; Liu, Kai; Deng, Tianwen; Yu, Qingtong; Deng, Wenwen; Yu, Jiangnan; Wang, Qilong; Xu, Ximing
      Pharmaceuticals (2022), 15 (9), 1059CODEN: PHARH2; ISSN:1424-8247. (MDPI AG)
      Due to the obstruction and heterogeneity of the blood-brain barrier, the clin. treatment of glioma has been extremely difficult. Isoliquiritigenin (ISL) exhibits antitumor effects, but its low soly. and bioavailability limit its application potential. Herein, we established a nanoscale hybrid membrane-derived system composed of erythrocytes and tumor cells. By encapsulating ISL in hybrid membrane nanoparticles, ISL is expected to be enhanced for the targeting and long-circulation in gliomas therapy. We fused erythrocytes with human glioma cells U251 and extd. the fusion membrane via hypotension, termed as hybrid membrane (HM). HM-camouflaged ISL nanoparticles (ISL@HM NPs) were prepd. and featured with FT-IR, SEM, TEM, and DLS particle anal. As the results concluded, the ISL active pharmaceutical ingredients (APIs) were successfully encapsulated with HM membranes, and the NPs loading efficiency was 38.9 ± 2.99% under max. entrapment efficiency. By comparing the IC50 of free ISL and NPs, we verified that the soly. and antitumor effect of NPs was markedly enhanced. We also investigated the mechanism of the antitumor effect of ISL@HM NPs, which revealed a marked inhibition of tumor cell proliferation and promotion of senescence and apoptosis of tumor cells of the formulation. In addn., the FSC and WB results examd. the effects of different concns. of ISL@HM NPs on tumor cell disruption and apoptotic protein expression. Finally, it can be concluded that hybridized membrane-derived nanoparticles could prominently increase the soly. of insol. materials (as ISL), and also enhance its targeting and antitumor effect.
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    47. 47
      Wildeboer, R. R.; Southern, P.; Pankhurst, Q. A. On the Reliable Measurement of Specific Absorption Rates and Intrinsic Loss Parameters in Magnetic Hyperthermia Materials. J. Phys. D. Appl. Phys. 2014, 47 (49), 495003,  DOI: 10.1088/0022-3727/47/49/495003
      47
      On the reliable measurement of specific absorption rates and intrinsic loss parameters in magnetic hyperthermia materials
      Wildeboer, R. R.; Southern, P.; Pankhurst, Q. A.
      Journal of Physics D: Applied Physics (2014), 47 (49), 495003/1-495003/14, 14 pp.CODEN: JPAPBE; ISSN:0022-3727. (IOP Publishing Ltd.)
      A review. In the clin. application of magnetic hyperthermia, the heat generated by magnetic nanoparticles in an alternating magnetic field is used as a cancer treatment. The heating ability of the particles is quantified by the specific absorption rate (SAR), an extrinsic parameter based on the clin. response characteristic of power delivered per unit mass, and by the intrinsic loss parameter (ILP), an intrinsic parameter based on the heating capacity of the material. Even though both the SAR and ILP are widely used as comparative design parameters, they are almost always measured in non-adiabatic systems that make accurate measurements difficult. We present here the results of a systematic review of measurement methods for both SAR and ILP, leading to recommendations for a standardised, simple and reliable method for measurements using non-adiabatic systems. In a representative survey of 50 retrieved datasets taken from published papers, the derived SAR or ILP was found to be more than 5% overestimated in 24% of cases and more than 5% underestimated in 52% of cases.
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    48. 48
      Marino, A.; Camponovo, A.; Degl’Innocenti, A.; Bartolucci, M.; Tapeinos, C.; Martinelli, C.; De Pasquale, D.; Santoro, F.; Mollo, V.; Arai, S.; Suzuki, M.; Harada, Y.; Petretto, A.; Ciofani, G. Multifunctional Temozolomide-Loaded Lipid Superparamagnetic Nanovectors: Dual Targeting and Disintegration of Glioblastoma Spheroids by Synergic Chemotherapy and Hyperthermia Treatment. Nanoscale 2019, 11 (44), 21227– 21248,  DOI: 10.1039/C9NR07976A
      48
      Multifunctional temozolomide-loaded lipid superparamagnetic nanovectors: dual targeting and disintegration of glioblastoma spheroids by synergic chemotherapy and hyperthermia treatment
      Marino, Attilio; Camponovo, Alice; Degl'Innocenti, Andrea; Bartolucci, Martina; Tapeinos, Christos; Martinelli, Chiara; De Pasquale, Daniele; Santoro, Francesca; Mollo, Valentina; Arai, Satoshi; Suzuki, Madoka; Harada, Yoshie; Petretto, Andrea; Ciofani, Gianni
      Nanoscale (2019), 11 (44), 21227-21248CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
      Aiming at finding new solns. for fighting glioblastoma multiforme, one of the most aggressive and lethal human cancer, here an in vitro validation of multifunctional nanovectors for drug delivery and hyperthermia therapy is proposed. Hybrid magnetic lipid nanoparticles have been fully characterized and tested on a multi-cellular complex model resembling the tumor microenvironment. Investigations of cancer therapy based on a phys. approach (namely hyperthermia) and on a pharmaceutical approach (by exploiting the chemotherapeutic drug temozolomide) have been extensively carried out, by evaluating its antiproliferative and pro-apoptotic effects on 3D models of glioblastoma multiforme. A systematic study of transcytosis and endocytosis mechanisms has been moreover performed with multiple complimentary investigations, besides a detailed description of local temp. increments following hyperthermia application. Finally, an in-depth proteomic anal. corroborated the obtained findings, which can be summarized in the prepn. of a versatile, multifunctional, and effective nanoplatform able to overcome the blood-brain barrier and to induce powerful anti-cancer effects on in vitro complex models.
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    49. 49
      Avrutsky, M. I.; Troy, C. M. Caspase-9: A Multimodal Therapeutic Target with Diverse Cellular Expression in Human Disease. Front. Pharmacol. 2021, 12 (July), 1– 17,  DOI: 10.3389/fphar.2021.701301
      There is no corresponding record for this reference.
    50. 50
      Bruderer, R.; Bernhardt, O. M.; Gandhi, T.; Miladinović, S. M.; Cheng, L. Y.; Messner, S.; Ehrenberger, T.; Zanotelli, V.; Butscheid, Y.; Escher, C.; Vitek, O.; Rinner, O.; Reiter, L. Extending the Limits of Quantitative Proteome Profiling with Data-Independent Acquisition and Application to Acetaminophen-Treated Three-Dimensional Liver Microtissues. Mol. Cell. Proteomics 2015, 14 (5), 1400– 1410,  DOI: 10.1074/mcp.M114.044305
      50
      Extending the Limits of Quantitative Proteome Profiling with Data-Independent Acquisition and Application to Acetaminophen-Treated Three-Dimensional Liver Microtissues
      Bruderer, Roland; Bernhardt, Oliver M.; Gandhi, Tejas; Miladinovic, Sasa M.; Cheng, Lin-Yang; Messner, Simon; Ehrenberger, Tobias; Zanotelli, Vito; Butscheid, Yulia; Escher, Claudia; Vitek, Olga; Rinner, Oliver; Reiter, Lukas
      Molecular & Cellular Proteomics (2015), 14 (5), 1400-1410CODEN: MCPOBS; ISSN:1535-9484. (American Society for Biochemistry and Molecular Biology)
      Our findings imply that DIA should be the preferred method for quant. protein profiling.
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    51. 51
      Tyanova, S.; Temu, T.; Sinitcyn, P.; Carlson, A.; Hein, M. Y.; Geiger, T.; Mann, M.; Cox, J. The Perseus Computational Platform for Comprehensive Analysis of (Prote)Omics Data. Nat. Methods 2016, 13 (9), 731– 740,  DOI: 10.1038/nmeth.3901
      51
      The Perseus computational platform for comprehensive analysis of (prote)omics data
      Tyanova, Stefka; Temu, Tikira; Sinitcyn, Pavel; Carlson, Arthur; Hein, Marco Y.; Geiger, Tamar; Mann, Matthias; Cox, Juergen
      Nature Methods (2016), 13 (9), 731-740CODEN: NMAEA3; ISSN:1548-7091. (Nature Publishing Group)
      A main bottleneck in proteomics is the downstream biol. anal. of highly multivariate quant. protein abundance data generated using mass-spectrometry-based anal. We developed the Perseus software platform (http://www.perseus-framework.org) to support biol. and biomedical researchers in interpreting protein quantification, interaction and post-translational modification data. Perseus contains a comprehensive portfolio of statistical tools for high-dimensional omics data anal. covering normalization, pattern recognition, time-series anal., cross-omics comparisons and multiple-hypothesis testing. A machine learning module supports the classification and validation of patient groups for diagnosis and prognosis, and it also detects predictive protein signatures. Central to Perseus is a user-friendly, interactive workflow environment that provides complete documentation of computational methods used in a publication. All activities in Perseus are realized as plugins, and users can extend the software by programming their own, which can be shared through a plugin store. We anticipate that Perseus's arsenal of algorithms and its intuitive usability will empower interdisciplinary anal. of complex large data sets.
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    52. 52
      Nica, V.; Sauer, H. M.; Embs, J.; Hempelmann, R. Calorimetric Method for the Determination of Curie Temperatures of Magnetic Nanoparticles in Dispersion. J. Phys.: Condens. Matter 2008, 20 (20), 204115,  DOI: 10.1088/0953-8984/20/20/204115
      52
      Calorimetric method for the determination of Curie temperatures of magnetic nanoparticles in dispersion
      Nica, V.; Sauer, H. M.; Embs, J.; Hempelmann, R.
      Journal of Physics: Condensed Matter (2008), 20 (20), 204115/1-204115/5CODEN: JCOMEL; ISSN:0953-8984. (Institute of Physics Publishing)
      MnxZn1-xFe2O4-based magnetic fluids with x = 0.1-0.9 were synthesized by copptn. The samples are heated in a radio frequency (rf) magnetic field using an radiofrequency generator at different powers, and the temp. is measured as function of time using an optical thermometer. The heating effect of the dispersed magnetic nanoparticles is proportional to the imaginary part of the dynamic magnetic susceptibility of the ferrofluid, a quantity that depends on the temp. through the magnetization of the ferrite nanoparticles and the Neel or Brownian relaxation times, resp. The authors propose an extrapolation method to actuate the Curie temps. of the dispersed magnetic nanoparticles. By appropriate fitting functions for (dT/dt) vs. T for both the heating and the cooling process, the authors deduce the Curie temp. of the samples under study. For MnxZn1-xFe2O4-based magnetic nanoparticles the Curie temps. decrease with increasing Zn content. They turn out to be lower than the literature values for bulk MnxZn1-xFe2O4, a phenomenon which is generally obsd. for phase transitions of nanocryst. materials.
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    53. 53
      Salazar-Alvarez, G.; Lidbaum, H.; López-Ortega, A.; Estrader, M.; Leifer, K.; Sort, J.; Suriñach, S.; Baró, M. D.; Nogués, J. Two-, Three-, and Four-Component Magnetic Multilayer Onion Nanoparticles Based on Iron Oxides and Manganese Oxides. J. Am. Chem. Soc. 2011, 133 (42), 16738– 16741,  DOI: 10.1021/ja205810t
      53
      Two-, Three-, and Four-Component Magnetic Multilayer Onion Nanoparticles Based on Iron Oxides and Manganese Oxides
      Salazar-Alvarez, German; Lidbaum, Hans; Lopez-Ortega, Alberto; Estrader, Marta; Leifer, Klaus; Sort, Jordi; Surinach, Santiago; Baro, Maria Dolors; Nogues, Josep
      Journal of the American Chemical Society (2011), 133 (42), 16738-16741CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Magnetic multilayered, onion-like, heterostructured nanoparticles are interesting model systems for studying magnetic exchange coupling phenomena. The authors synthesized heterostructured magnetic nanoparticles composed of two, three, or four components using iron oxide seeds for the subsequent deposition of manganese oxide. The MnO layer was allowed either to passivate fully in air to form an outer layer of Mn3O4 or to oxidize partially to form MnO|Mn3O4 double layers. Through control of the degree of passivation of the seeds, particles with up to four different magnetic layers can be obtained (i.e., FeO|Fe3O4|MnO|Mn3O4). Magnetic characterization of the samples confirmed the presence of the different magnetic layers.
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    54. 54
      Grosvenor, A. P.; Kobe, B. A.; Biesinger, M. C.; McIntyre, N. S. Investigation of Multiplet Splitting of Fe 2p XPS Spectra and Bonding in Iron Compounds. Surf. Interface Anal. 2004, 36 (12), 1564– 1574,  DOI: 10.1002/sia.1984
      54
      Investigation of multiplet splitting of Fe 2p XPS spectra and bonding in iron compounds
      Grosvenor, A. P.; Kobe, B. A.; Biesinger, M. C.; McIntyre, N. S.
      Surface and Interface Analysis (2004), 36 (12), 1564-1574CODEN: SIANDQ; ISSN:0142-2421. (John Wiley & Sons Ltd.)
      Ferrous (Fe2+) and ferric (Fe3+) compds. were studied by XPS to det. the usefulness of calcd. multiplet peaks to fit high-resoln. Fe 2p3/2 spectra from high-spin compds. The multiplets fit most spectra well, particularly when contributions attributed to surface peaks and shake-up satellites were included. This information was useful for fitting of the complex Fe 2p3/2 spectra for Fe3O4 where both Fe2+ and Fe3+ species are present. As the ionic bond character of the Fe-ligand bond increased, the binding energy assocd. with either the ferrous or ferric 2p3/2 photoelectron peak increased. This is due to the decrease in shielding of the Fe cation by the more increasingly electroneg. ligands. Also the difference in energy between a high-spin Fe 2p3/2 peak and its corresponding shake-up satellite peak increased as the electronegativity of the ligand increased. The extrinsic loss spectra for Fe oxides are reported; these are as characteristic of each species as are the photoelectron peaks.
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    55. 55
      Gupta, R. P.; Sen, S. K. Calculation of Multiplet Structure of Core p-Vacancy Levels. II. Phys. Rev. B 1975, 12 (1), 15– 19,  DOI: 10.1103/PhysRevB.12.15
      55
      Calculation of multiplet structure of core p-vacancy levels. II
      Gupta, R. P.; Sen, S. K.
      Physical Review B: Solid State (1975), 12 (1), 15-19CODEN: PLRBAQ; ISSN:0556-2805.
      The multiplet structure of core 2p-vacancy levels for 36 ions belonging to 3d transition metals were calcd. and their plots presented. Only the ground-state configuration 2p53dn (n = 1,...,9) is considered for each ion. The spin-orbit interaction was incorporated exactly, but the crystal-field effect is ignored. While there is general agreement with the available exptl. works, higher-energy resolution in x-ray-photoelectron measurements is necessary for detailed comparison of the spectra presented here. On the theor. side inclusion of crystal field appears to be important. One should go beyond single-configuration approxn. to have the obsd. satellite structure in 2p-x-ray-photoelectron spectra appear in the calcns.
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    56. 56
      McIntyre, N. S.; Zetaruk, D. G. X-Ray Photoelectron Spectroscopic Studies of Iron Oxides. Anal. Chem. 1977, 49 (11), 1521– 1529,  DOI: 10.1021/ac50019a016
      56
      X-ray photoelectron spectroscopic studies of iron oxides
      McIntyre, N. S.; Zetaruk, D. G.
      Analytical Chemistry (1977), 49 (11), 1521-9CODEN: ANCHAM; ISSN:0003-2700.
      Core line x-ray photoelectron (XP) spectra are reported for the iron compds. αFe2O3, γFe2O3, αFeOOH, NiFe2O4, CoFe2O4, Fe3O4, and FeO. Such XP spectra are of particular value in characterizing surface films contg. iron corrosion products. For the oxides and hydroxides FeOOH, FeO and Fe3O4, the obsd. chem. shift is sufficiently large to permit these species to be uniquely distinguished from other iron oxides. In Fe3O4, both ferrous and ferric oxidn. states are obsd. and their relative concns. can be detd. using spectral line fitting procedures. The oxides αFe2O3, γFe2O3, NiFe2O4, and CoFe2O4 have almost identical core binding energies, but the multiplet splitting patterns obsd. in their Fe(2p) core levels are sufficiently different to permit their use for characterization. The Fe(2p) multiplet pattern obsd. for αFe2O3 agrees well with splitting previously calcd. for the free Fe3+ ion. Valence band spectra for γFe2O3, αFe2O3, Fe3O4 and FeO are reported and band assignment are made. The effect of ion bombardment of iron oxide surfaces was studied and evidence for the redn. of ferric oxides to FeO is presented.
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    57. 57
      Pratt, A. R.; Muir, I. J.; Nesbitt, H. W. X-Ray Photoelectron and Auger Electron Spectroscopic Studies of Pyrrhotite and Mechanism of Air Oxidation. Geochim. Cosmochim. Acta 1994, 58 (2), 827– 841,  DOI: 10.1016/0016-7037(94)90508-8
      57
      X-ray photoelectron and Auger electron spectroscopic studies of pyrrhotite and mechanism of air oxidation
      Pratt, A. R.; Muir, I. J.; Nesbitt, H. W.
      Geochimica et Cosmochimica Acta (1994), 58 (2), 827-41CODEN: GCACAK; ISSN:0016-7037.
      Pyrrhotite (Fe7S8) fractured under high vacuum (10-7 Pa) and reacted with air for 6.5 and 50 h was analyzed using XPS and Auger Electron Spectroscopy (AES). XPS iron data from fresh surfaces indicate 32% Fe(III) and 68% Fe(II), both bonded to sulfur. The result agrees closely with stoichiometry which suggests 29% Fe(III) in the pyrrhotite studies. This is the first spectroscopic evidence to indicate Fe(III) in pyrrhotite. Sulfur is present primarily as monosulfide (S2-), with minor amts. of disulfide (S22-) and polysulfide (Sn2-). XPS examn. of 6.5 h air-oxidized surfaces indicates 58% Fe(III) and 42% Fe(II). Fe(III) is bonded to oxygen and most Fe(II) remains bonded to sulfur. XPS iron and oxygen data suggest a Fe(III)-oxyhydroxide to be the species that formed. Sulfur spectra demonstrate a range of oxidn. states from S2- (monosulfide) to S6+ (sulfate). AES compositional depth profiles of air-oxidized surfaces display three compositional zones. After 50 h of air oxidn. the outermost layer is less than 10 Å, oxygen-rich, and sulfur depleted. Immediately below the O-rich layer exists an Fe-deficient, S-rich layer that displays a continuous, gradual decrease in S/Fe from the O-rich zone to that of the unaltered pyrrhotite. Quantification of depth profiles utilizing the sequential layer sputtering model (SLS) indicate alteration trends correspond compositionally to FeO1.5, FeS2, Fe2S3, and Fe7S8. Compositional zones develop by electron and iron migration towards the oxidized surface. Mol. oxygen, initially taken onto the surface, is reduced to O2- probably by electron transfer from the pyrrhotite interior, and is facilitated by rapid electron exchange between Fe(III) and Fe(II) of the bulk solid. Vacancies inherent to nonstoichiometric pyrrhotite probably promote diffusion of iron to the surface resulting in the formation of iron oxyhydroxide species.
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    58. 58
      Biesinger, M. C.; Payne, B. P.; Grosvenor, A. P.; Lau, L. W. M.; Gerson, A. R.; Smart, R. S. C. Resolving Surface Chemical States in XPS Analysis of First Row Transition Metals, Oxides and Hydroxides: Cr, Mn, Fe, Co and Ni. Appl. Surf. Sci. 2011, 257 (7), 2717– 2730,  DOI: 10.1016/j.apsusc.2010.10.051
      58
      Resolving surface chemical states in XPS analysis of first row transition metals, oxides and hydroxides: Cr, Mn, Fe, Co and Ni
      Biesinger, Mark C.; Payne, Brad P.; Grosvenor, Andrew P.; Lau, Leo W. M.; Gerson, Andrea R.; Smart, Roger St. C.
      Applied Surface Science (2011), 257 (7), 2717-2730CODEN: ASUSEE; ISSN:0169-4332. (Elsevier B.V.)
      Chem. state x-ray photoelectron spectroscopic anal. of 1st row transition metals and their oxides and hydroxides is challenging due to the complexity of their 2p spectra resulting from peak asymmetries, complex multiplet splitting, shake-up and plasmon loss structure, and uncertain, overlapping binding energies. The previous paper in which the authors examd. Sc, Ti, V, Cu and Zn species, showed that all the values of the spectral fitting parameters for each specific species, i.e. binding energy (eV), full wide at half max. (FWHM) value (eV) for each pass energy, spin-orbit splitting values and asym. peak shape fitting parameters, are not all normally provided in the literature and data bases, and are necessary for reproducible, quant. chem. state anal. A more consistent, practical and effective approach to curve fitting was developed based on a combination of (1) std. spectra from quality ref. samples, (2) a survey of appropriate literature databases and/or a compilation of literature refs. and (3) specific literature refs. where fitting procedures are available. This paper extends this approach to the chem. states of Cr, Mn, Fe, Co and Ni metals, and various oxides and hydroxides where intense, complex multiplet splitting in many of the chem. states of these elements poses unique difficulties for chem. state anal. The curve fitting procedures proposed use the same criteria as proposed previously but with the addnl. complexity of fitting of multiplet split spectra which was done based on spectra of numerous ref. materials and theor. XPS modeling of these transition metal species. Binding energies, FWHM values, asym. peak shape fitting parameters, multiplet peak sepn. and peak area percentages are presented. The procedures developed can be used to remove uncertainties in the anal. of surface states in nanoparticles, corrosion, catalysis and surface-engineered materials.
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    59. 59
      Biesinger, M. C.; Lau, L. W. M.; Gerson, A. R.; Smart, R. S. C. Resolving Surface Chemical States in XPS Analysis of First Row Transition Metals, Oxides and Hydroxides: Sc, Ti, V, Cu and Zn. Appl. Surf. Sci. 2010, 257 (3), 887– 898,  DOI: 10.1016/j.apsusc.2010.07.086
      59
      Resolving surface chemical states in XPS analysis of first row transition metals, oxides and hydroxides: Sc, Ti, V, Cu and Zn
      Biesinger, Mark C.; Lau, Leo W. M.; Gerson, Andrea R.; Smart, Roger St. C.
      Applied Surface Science (2010), 257 (3), 887-898CODEN: ASUSEE; ISSN:0169-4332. (Elsevier B.V.)
      Chem. state x-ray photoelectron spectroscopic anal. of 1st row transition metals and their oxides and hydroxides is challenging due to the complexity of the 2p spectra resulting from peak asymmetries, complex multiplet splitting, shake-up and plasmon loss structure, and uncertain, overlapping binding energies. Current literature shows that all values necessary for reproducible, quant. chem. state anal. are usually not provided. A more consistent, practical and effective approach to curve-fitting the various chem. states in a variety of Sc, Ti, V, Cu and Zn metals, oxides and hydroxides is reported. The curve-fitting procedures proposed are based on a combination of (1) std. spectra from quality ref. samples, (2) a survey of appropriate literature databases and/or a compilation of the literature refs., and (3) specific literature refs. where fitting procedures are available. Binding energies, full-width at half max. (FWHM) values, spin-orbit splitting values, asym. peak-shape fitting parameters, and, for Cu and Zn, Auger parameters values are presented. The quantification procedure for Cu species details the use of the shake-up satellites for Cu(II)-contg. compds. and the exact binding energies of the Cu(0) and Cu(I) peaks. The use of the modified Auger parameter for Cu and Zn species allows for corroborating evidence when there is uncertainty in the binding energy assignment. These procedures can remove uncertainties in anal. of surface states in nano-particles, corrosion, catalysis and surface-engineered materials.
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    60. 60
      Tanuma, S.; Powell, C. J.; Penn, D. R. Electron Inelastic Mean Free Paths in Solids at Low Energies. J. Electron Spectrosc. Relat. Phenom. 1990, 52 (C), 285– 291,  DOI: 10.1016/0368-2048(90)85024-4
      60
      Electron inelastic mean free paths in solids at low energies
      Tanuma, S.; Powell, C. J.; Penn, D. R.
      Journal of Electron Spectroscopy and Related Phenomena (1990), 52 (), 285-91CODEN: JESRAW; ISSN:0368-2048.
      Electron inelastic mean free path (IMFPs) were calcd. for 50-200 eV electrons in 31 materials (27 elements and 4 compds.). These calcns. extend those previously reported for 200-2000 eV electrons in the same materials but avoid an approxn. valid for electron energies above 200 eV. IMFP results are presented in this paper for magnesium, aluminum, silicon, nickel, copper, and gold. The IMFP dependence on electron energy in the range 50-200 eV varies considerably from material to material; these variations are assocd. with substantial differences in the electron energy-loss functions amongst the materials. The general IMFP formula derived earlier was extended to describe the calcd. IMFPs over the 50-2000 eV energy range.
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    61. 61
      Song, Q.; Zhang, Z. J. Controlled Synthesis and Magnetic Properties of Bimagnetic Spinel Ferrite CoFe2O4 and MnFe2O 4 Nanocrystals with Core-Shell Architecture. J. Am. Chem. Soc. 2012, 134 (24), 10182– 10190,  DOI: 10.1021/ja302856z
      61
      Controlled Synthesis and Magnetic Properties of Bimagnetic Spinel Ferrite CoFe2O4 and MnFe2O4 Nanocrystals with Core-Shell Architecture
      Song, Qing; Zhang, Z. John
      Journal of the American Chemical Society (2012), 134 (24), 10182-10190CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      A combination of hard phase CoFe2O4 and soft phase MnFe2O4 as the bimagnetic nanocrystals in a core-shell architecture has been synthesized, and their magnetic properties have been systematically studied. Both HRTEM and EDS results confirmed the formation of bimagnetic core-shell structured nanocrystals. On the basis of the systematic and comparative studies of the magnetic properties of a mech. mixt. of pure CoFe2O4 and MnFe2O4 nanocrystals, chem. mixed Co1-xMnxFe2O4 nanocrystals, and bimagnetic core-shell CoFe2O4@MnFe2O4 and MnFe2O4@CoFe2O4 nanocrystals, the bimagnetic core-shell nanocrystals show very unique magnetic properties, such as the blocking temp. and coercivity. Our results show that the coercivity correlates with the vol. fraction of the soft phase as the theor. hard-soft phase model has suggested. Furthermore, switching the hard phase CoFe2O4 from the core to the shell shows great changes in the coercivity of the nanocrystals. The bimagnetic core-shell nanocrystals evidently demonstrate the rational design capability to sep. control the blocking temp. and the coercivity in magnetic nanocrystals by varying the materials, their combination, and the vol. ratio between the core and the shell and by switching hard or soft phase materials between the core and shell. Such controls via a bimagnetic core-shell architecture are highly desirable for magnetic nanocrystals in various applications.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XnsVeru7g%253D&md5=28b3204a4d19df4f643ebc281f6ea181
    62. 62
      Juhin, A.; López-Ortega, A.; Sikora, M.; Carvallo, C.; Estrader, M.; Estradé, S.; Peiró, F.; Baró, M. D.; Sainctavit, P.; Glatzel, P.; Nogués, J. Direct Evidence for an Interdiffused Intermediate Layer in Bi-Magnetic Core-Shell Nanoparticles. Nanoscale 2014, 6 (20), 11911– 11920,  DOI: 10.1039/C4NR02886D
      62
      Direct evidence for an interdiffused intermediate layer in bi-magnetic core-shell nanoparticles
      Juhin, Amelie; Lopez-Ortega, Alberto; Sikora, Marcin; Carvallo, Claire; Estrader, Marta; Estrade, Sonia; Peiro, Francesca; Baro, Maria Dolors; Sainctavit, Philippe; Glatzel, Pieter; Nogues, Josep
      Nanoscale (2014), 6 (20), 11911-11920CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
      Core-shell nanoparticles attract continuously growing interest due to their numerous applications, which are driven by the possibility of tuning their functionalities by adjusting structural and morphol. parameters. However, despite the crit. role interdiffused interfaces may have in the properties, these are usually only estd. in indirect ways. Here we directly evidence the existence of a 1.1 nm thick (Fe,Mn)3O4 interdiffused intermediate shell in nominally γ-Fe2O3-Mn3O4 core-shell nanoparticles using resonant inelastic X-ray scattering spectroscopy combined with magnetic CD (RIXS-MCD). This recently developed magneto-spectroscopic probe exploits the unique advantages of hard X-rays (i.e., chem. selectivity, bulk sensitivity, and low self-absorption at the K pre-edge) and can be advantageously combined with transmission electron microscopy and electron energy loss spectroscopy to quant. elucidate the buried internal structure of complex objects. The detailed information on the structure of the nanoparticles allows understanding the influence of the interface quality on the magnetic properties.
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    63. 63
      Kubisztal, M.; Kubisztal, J.; Karolus, M.; Prusik, K.; Haneczok, G. Evolution of Frozen Magnetic State in Co-Precipitated ZnδCo1-δFe2O4 (0 ≤ δ ≤ 1) Ferrite Nanopowders. J. Magn. Magn. Mater. 2018, 454, 368– 374,  DOI: 10.1016/j.jmmm.2018.02.001
      63
      Evolution of frozen magnetic state in co-precipitated ZnδCo1-δFe2O4 (0 ≤ δ ≤ 1) ferrite nanopowders
      Kubisztal, M.; Kubisztal, J.; Karolus, M.; Prusik, K.; Haneczok, G.
      Journal of Magnetism and Magnetic Materials (2018), 454 (), 368-374CODEN: JMMMDC; ISSN:0304-8853. (Elsevier B.V.)
      The evolution of frozen magnetic state of ZnδCo1-δFe2O4 (0 ≤ δ ≤ 1) ferrite nanoparticles was studied by applying vibrating sample magnetometer measurements in temp. range 5-350 K and magnetic fields up to 7 T. It was shown that gradual conversion from the inverse spinel (δ = 0) to the normal one (δ = 1.0) is correlated with a drop of freezing temp. Tf (corresponding to blocking of mean magnetic moment of the system) from 238 K (δ = 0) to 9 K (δ = 1.0) and with a decrease of magnetic anisotropy const. K1 from about 8 · 105 J/m3 to about 3 · 105 J/m3. The percolation threshold predicted for bulk ferrites at 1 - δ ≈ 0.33 was obsd. as a significant weakness of ferrimagnetic coupling. In this case magnetization curves, detd. according to the zero field cooling protocol, reveal two distinct maxima indicating that the system splits into two assemblies with specific ions distribution between A and B sites.
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    64. 64
      Gneveckow, U.; Jordan, A.; Scholz, R.; Brüß, V.; Waldöfner, N.; Ricke, J.; Feussner, A.; Hildebrandt, B.; Rau, B.; Wust, P. Description and Characterization of the Novel Hyperthermia- and Thermoablation-System MFH®300F for Clinical Magnetic Fluid Hyperthermia. Med. Phys. 2004, 31 (6), 1444– 1451,  DOI: 10.1118/1.1748629
      64
      Description and characterization of the novel hyperthermia- and thermoablation-system MFH 300F for clinical magnetic fluid hyperthermia
      Gneveckow Uwe; Jordan Andreas; Scholz Regina; Bruss Volker; Waldofner Norbert; Ricke Jens; Feussner Annelie; Hildebrandt Bert; Rau Beate; Wust Peter
      Medical physics (2004), 31 (6), 1444-51 ISSN:0094-2405.
      Magnetic fluid hyperthermia (MFH) is a new approach to deposit heat power in deep tissues by overcoming limitations of conventional heat treatments. After infiltration of the target tissue with nanosized magnetic particles, the power of an alternating magnetic field is transformed into heat. The combination of the 100 kHz magnetic field applicator MFH 300F and the magnetofluid (MF), which both are designed for medical use, is investigated with respect to its dosage recommendations and clinical applicability. We found a magnetic field strength of up to 18 kA/m in a cylindrical treatment area of 20 cm diameter and aperture height up to 300 mm. The specific absorption rate (SAR) can be controlled directly by the magnetic field strength during the treatment. The relationship between magnetic field strength and the iron normalized SAR (SAR(Fe)) is only slightly depending on the concentration of the MF and can be used for planning the target SAR. The achievable energy absorption rates of the MF distributed in the tissue is sufficient for either hyperthermia or thermoablation. The fluid has a visible contrast in therapeutic concentrations on a CT scanner and can be detected down to 0.01 g/l Fe in the MRI. The system has proved its capability and practicability for heat treatment in deep regions of the human body.
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    65. 65
      Liu, X.; Zhang, Y.; Wang, Y.; Zhu, W.; Li, G.; Ma, X.; Zhang, Y.; Chen, S.; Tiwari, S.; Shi, K.; Zhang, S.; Fan, H. M.; Zhao, Y. X.; Liang, X. J. Comprehensive Understanding of Magnetic Hyperthermia for Improving Antitumor Therapeutic Efficacy. Theranostics 2020, 10 (8), 3793– 3815,  DOI: 10.7150/thno.40805
      65
      Comprehensive understanding of magnetic hyperthermia for improving antitumor therapeutic efficacy
      Liu, Xiaoli; Zhang, Yifan; Wang, Yanyun; Zhu, Wenjing; Li, Galong; Ma, Xiaowei; Zhang, Yihan; Chen, Shizhu; Tiwari, Shivani; Shi, Kejian; Zhang, Shouwen; Fan, Hai Ming; Zhao, Yong Xiang; Liang, Xing-Jie
      Theranostics (2020), 10 (8), 3793-3815CODEN: THERDS; ISSN:1838-7640. (Ivyspring International Publisher)
      A review. Magnetic hyperthermia (MH) has been introduced clin. as an alternative approach for the focal treatment of tumors. MH utilizes the heat generated by the magnetic nanoparticles (MNPs) when subjected to an alternating magnetic field (AMF). It has become an important topic in the nanomedical field due to their multitudes of advantages towards effective antitumor therapy such as high biosafety, deep tissue penetration, and targeted selective tumor killing. However, in order for MH to progress and to realize its paramount potential as an alternative choice for cancer treatment, tremendous challenges have to be overcome. Thus, the efficiency of MH therapy needs enhancement. In its recent 60-yr of history, the field of MH has focused primarily on heating using MNPs for therapeutic applications. Increasing the thermal conversion efficiency of MNPs is the fundamental strategy for improving therapeutic efficacy. Recently, emerging exptl. evidence indicates that MNPs-MH produces nano-scale heat effects without macroscopic temp. rise. A deep understanding of the effect of this localized induction heat for the destruction of subcellular/cellular structures further supports the efficacy of MH in improving therapeutic therapy. In this review, the currently available strategies for improving the antitumor therapeutic efficacy of MNPs-MH will be discussed. Firstly, the recent advancements in engineering MNP size, compn., shape, and surface to significantly improve their energy dissipation rates will be explored. Secondly, the latest studies depicting the effect of local induction heat for selectively disrupting cells/intracellular structures will be examd. Thirdly, strategies to enhance the therapeutics by combining MH therapy with chemotherapy, radiotherapy, immunotherapy, photothermal/photodynamic therapy (PDT), and gene therapy will be reviewed. Lastly, the prospect and significant challenges in MH-based antitumor therapy will be discussed. This review is to provide a comprehensive understanding of MH for improving antitumor therapeutic efficacy, which would be of utmost benefit towards guiding the users and for the future development of MNPs-MH towards successful application in medicine.
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    66. 66
      Noh, S. H.; Na, W.; Jang, J. T.; Lee, J. H.; Lee, E. J.; Moon, S. H.; Lim, Y.; Shin, J. S.; Cheon, J. Nanoscale Magnetism Control via Surface and Exchange Anisotropy for Optimized Ferrimagnetic Hysteresis. Nano Lett. 2012, 12 (7), 3716– 3721,  DOI: 10.1021/nl301499u
      66
      Nanoscale magnetism control via surface and exchange anisotropy for optimized ferrimagnetic hysteresis
      Noh, Seung-hyun; Na, Wonjun; Jang, Jung-tak; Lee, Jae-Hyun; Lee, Eun Jung; Moon, Seung Ho; Lim, Yongjun; Shin, Jeon-Soo; Cheon, Jinwoo
      Nano Letters (2012), 12 (7), 3716-3721CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
      With the aim of controlling nanoscale magnetism, we demonstrate an approach encompassing concepts of surface and exchange anisotropy while reflecting size, shape, and structural hybridization of nanoparticles. We visualize that cube has higher magnetization value than sphere with highest coercivity at 60 nm. Its hybridization into core-shell (CS) structure brings about a 14-fold increase in the coercivity with an exceptional energy conversion of magnetic field into thermal energy of 10600 W/g, the largest reported to date. Such capability of the CS-cube is highly effective for drug resistant cancer cell treatment.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XovFWgu7g%253D&md5=958fb89c343e1bf3a1b99eb52b3b342b
    67. 67
      Balk, M.; Haus, T.; Band, J.; Unterweger, H.; Schreiber, E.; Friedrich, R. P.; Alexiou, C.; Gostian, A. O. Cellular Spion Uptake and Toxicity in Various Head and Neck Cancer Cell Lines. Nanomaterials 2021, 11 (3), 726,  DOI: 10.3390/nano11030726
      67
      Cellular SPION uptake and toxicity in various head and neck cancer cell lines
      Balk, Matthias; Haus, Theresa; Band, Julia; Unterweger, Harald; Schreiber, Eveline; Friedrich, Ralf P.; Alexiou, Christoph; Gostian, Antoniu-Oreste
      Nanomaterials (2021), 11 (3), 726CODEN: NANOKO; ISSN:2079-4991. (MDPI AG)
      Superparamagnetic iron oxide nanoparticles (SPIONs) feature distinct magnetic properties that make them useful and effective tools for various diagnostic, therapeutic and theranostic applications. In particular, their use in magnetic drug targeting (MDT) promises to be an effective approach for the treatment of various diseases such as cancer. At the cellular level, SPION uptake, along with SPION-mediated toxicity, represents the most important prerequisite for successful application. Thus, the present study dets. SPION uptake, toxicity and biocompatibility in human head and neck tumor cell lines of the tongue, pharynx and salivary gland. Using magnetic susceptibility measurements, microscopy, at. emission spectroscopy, flow cytometry, and plasma coagulation, we analyzed the magnetic properties, cellular uptake and biocompatibility of two different SPION types in the presence and absence of external magnetic fields. Incubation of cells with lauric acid and human serum albumin-coated nanoparticles (SPIONLA-HSA) resulted in substantial particle uptake with low cytotoxicity. In contrast, uptake of lauric acid-coated nanoparticles (SPIONLA) was substantially increased but accompanied by higher toxicity. The presence of an external magnetic field significantly increased cellular uptake of both particles, although cytotoxicity was not significantly increased in any of the cell lines. SPIONs coated with lauric acid and/or human serum albumin show different patterns of uptake and toxicity in response to an external magnetic field. Consequently, the results indicate the potential use of SPIONs as vehicles for MDT in head and neck cancer.
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    68. 68
      Chen, L.; Hong, W.; Ren, W.; Xu, T.; Qian, Z.; He, Z. Recent Progress in Targeted Delivery Vectors Based on Biomimetic Nanoparticles. Signal Transduct. Target. Ther. 2021, 6, 225,  DOI: 10.1038/s41392-021-00631-2
      68
      Recent progress in targeted delivery vectors based on biomimetic nanoparticles
      Chen Li; Hong Weiqi; Ren Wenyan; Xu Ting; Qian Zhiyong; He Zhiyao; Xu Ting; He Zhiyao
      Signal transduction and targeted therapy (2021), 6 (1), 225 ISSN:.
      Over the past decades, great interest has been given to biomimetic nanoparticles (BNPs) since the rise of targeted drug delivery systems and biomimetic nanotechnology. Biological vectors including cell membranes, extracellular vesicles (EVs), and viruses are considered promising candidates for targeted delivery owing to their biocompatibility and biodegradability. BNPs, the integration of biological vectors and functional agents, are anticipated to load cargos or camouflage synthetic nanoparticles to achieve targeted delivery. Despite their excellent intrinsic properties, natural vectors are deliberately modified to endow multiple functions such as good permeability, improved loading capability, and high specificity. Through structural modification and transformation of the vectors, they are pervasively utilized as more effective vehicles that can deliver contrast agents, chemotherapy drugs, nucleic acids, and genes to target sites for refractory disease therapy. This review summarizes recent advances in targeted delivery vectors based on cell membranes, EVs, and viruses, highlighting the potential applications of BNPs in the fields of biomedical imaging and therapy industry, as well as discussing the possibility of clinical translation and exploitation trend of these BNPs.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB2c7lsVaisw%253D%253D&md5=5298ef12434df3b722a8296ad015c48f
    69. 69
      Li, J.; Wang, X.; Zheng, D.; Lin, X.; Wei, Z.; Zhang, D.; Li, Z.; Zhang, Y.; Wu, M.; Liu, X. Cancer Cell Membrane-Coated Magnetic Nanoparticles for MR/NIR Fluorescence Dual-Modal Imaging and Photodynamic Therapy. Biomater. Sci. 2018, 6 (7), 1834– 1845,  DOI: 10.1039/C8BM00343B
      69
      Cancer cell membrane-coated magnetic nanoparticles for MR/NIR fluorescence dual-modal imaging and photodynamic therapy
      Li, Jiong; Wang, Xuandong; Zheng, Dongye; Lin, Xinyi; Wei, Zuwu; Zhang, Da; Li, Zhuanfang; Zhang, Yun; Wu, Ming; Liu, Xiaolong
      Biomaterials Science (2018), 6 (7), 1834-1845CODEN: BSICCH; ISSN:2047-4849. (Royal Society of Chemistry)
      Theranostic nanoprobes integrated with dual-modal imaging and therapeutic functions, such as photodynamic therapy (PDT), have exhibited significant potency in cancer treatments due to their high imaging accuracy and non-invasive advantages for cancer elimination. However, biocompatibility and highly efficient accumulation of these nanoprobes in tumor are still unsatisfactory for clin. application. In this study, a photosensitizer -loaded magnetic nanobead with surface further coated with a layer of cancer cell membrane (SSAP-Ce6@CCM) was designed to improve the biocompatibility and cellular uptake and ultimately achieve enhanced MR/NIR fluorescence imaging and PDT efficacy. Compared with similar nanobeads without CCM coating, SSAP-Ce6@CCM showed significantly enhanced cellular uptake, as evidenced by Prussian blue staining, confocal laser scanning microscopy (CLSM) and flow cytometric anal. Consequently, SSAP-Ce6@CCM displayed a more distinct MR/NIR imaging ability and more obvious photo-cytotoxicity towards cancer cells under 670 nm laser irradn. Furthermore, the enhanced PDT effect benefited from the surface coating of cancer cell membrane was demonstrated in SMMC-7721 tumor-bearing mice through tumor growth observation and tumor tissue pathol. examn. Therefore, this CCM-disguised nanobead that integrated the abilities of MR/NIR fluorescence dual-modal imaging and photodynamic therapy might be a promising theranostic platform for tumor treatment.
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    70. 70
      Weiss, I. M.; Muth, C.; Drumm, R.; Kirchner, H. O. K. Thermal Decomposition of the Amino Acids Glycine, Cysteine, Aspartic Acid, Asparagine, Glutamic Acid, Glutamine, Arginine and Histidine. BMC Biophys. 2018, 11, 2,  DOI: 10.1186/s13628-018-0042-4
      70
      Thermal decomposition of the amino acids glycine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine, arginine and histidine
      Weiss, Ingrid M.; Muth, Christina; Drumm, Robert; Kirchner, Helmut O. K.
      BMC Biophysics (2018), 11 (), 2/1-2/15CODEN: BBMIG8; ISSN:2046-1682. (BioMed Central Ltd.)
      The pathways of thermal instability of amino acids have been unknown. New mass spectrometric data allow unequivocal quant. identification of the decompn. products. Calorimetry, thermogravimetry and mass spectrometry were used to follow the thermal decompn. of the eight amino acids G, C, D, N, E, Q, R and H between 185 °C and 280 °C. Endothermic heats of decompn. between 72 and 151 kJ/mol are needed to form 12 to 70% volatile products. This process is neither melting nor sublimation. With exception of cysteine they emit mainly H2O, some NH3 and no CO2. Cysteine produces CO2 and little else. The reactions are described by polynomials, AA → a NH3 + b H2O + c CO2 + d H2S + e residue, with integer or half integer coeffs. The solid monomol. residues are rich in peptide bonds. Eight of the 20 std. amino acids decomp. at well-defined, characteristic temps., in contrast to commonly accepted knowledge. Products of decompn. are simple. The novel quant. results emphasize the impact of water and cyclic condensates with peptide bonds and put constraints on hypotheses of the origin, state and stability of amino acids in the range between 200 °C and 300 °C.
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    71. 71
      Athanasoulia, I. G.; Tarantili, P. A. Preparation and Characterization of Polyethylene Glycol/Poly(L-Lactic Acid) Blends. Pure Appl. Chem. 2017, 89 (1), 141– 152,  DOI: 10.1515/pac-2016-0919
      71
      Preparation and characterization of polyethylene glycol/poly(L-lactic acid) blends
      Athanasoulia, Ioanna-Georgia; Tarantili, Petroula A.
      Pure and Applied Chemistry (2017), 89 (1), 141-152CODEN: PACHAS; ISSN:0033-4545. (Walter de Gruyter, Inc.)
      The effect of incorporation of poly(ethylene glycol) (PEG) on thermomech. and hydrophilicity properties of poly(L-lactic acid) (PLLA) was investigated. PEG/PLLA blends, contg. 10, 20, 30 and 40 wt.% PEG, were prepd. by melt-extrusion in a co-rotating twin-screw extruder. By DSC anal., it was obsd. that the Tg of PLLA phase in PEG/PLLA blends decreased accompanied by a significant decrease in Tcc and increase in their melting enthalpy. Therefore, the addn. of PEG enhances the crystn. ability of PLLA phase due to its lubricating effect which increased mobility of PLLA chains. From TGA it was obsd. that low concns. of PEG (10 & 20 wt.%) increase the Tonset of thermal degrdn., probably due to improved heat resistance of the cryst. phase. At higher PEG content, the Tonset decreases, as the lubricating effect becomes the controlling mechanism for the initiation of degrdn. process. Decrease in tensile strength and modulus was recorded esp. in PLLA blends with PEG content higher than 20 wt.%. The elongation at break decreases reaching a max. at 20 wt.% PEG and then dropped again. To investigate the effect of PEG on the wetting ability of PLLA, water contact angle measurements were performed. The results indicate that the introduction of PEG lowers the contact angle values in PEG/PLLA film surfaces, as compared to pure PLLA, suggesting improved hydrophilic properties.
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    72. 72
      Xia, X.; Yang, M.; Wang, Y.; Zheng, Y.; Li, Q.; Chen, J.; Xia, Y. Quantifying the Coverage Density of Poly(Ethylene Glycol) Chains on the Surface of Gold Nanostructures. ACS Nano 2012, 6 (1), 512– 522,  DOI: 10.1021/nn2038516
      72
      Quantifying the Coverage Density of Poly(ethylene glycol) Chains on the Surface of Gold Nanostructures
      Xia, Xiaohu; Yang, Miaoxin; Wang, Yucai; Zheng, Yiqun; Li, Qingge; Chen, Jingyi; Xia, Younan
      ACS Nano (2012), 6 (1), 512-522CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      The coverage d. of poly(ethylene glycol) (PEG) is a key parameter in detg. the efficiency of PEGylation, a process pivotal to in vivo delivery and targeting of nanomaterials. Here we report four complementary methods for quantifying the coverage d. of PEG chains on various types of Au nanostructures by using a model system based on HS-PEG-NH2 with different mol. wts. Specifically, the methods involve reactions with fluorescamine and ninhydrin, as well as labeling with fluorescein isothiocyanate (FITC) and Cu2+ ions. The first two methods use conventional amine assays to measure the no. of unreacted HS-PEG-NH2 mols. left behind in the soln. after incubation with the Au nanostructures. The other two methods involve coupling between the terminal -NH2 groups of adsorbed -S-PEG-NH2 chains and FITC or a ligand for Cu2+ ion, and thus pertain to the "active" -NH2 groups on the surface of a Au nanostructure. We found that the coverage d. decreased as the length of PEG chains increased. A stronger binding affinity of the initial capping ligand to the Au surface tended to reduce the PEGylation efficiency by slowing down the ligand exchange process. For the Au nanostructures and capping ligands we have tested, the PEGylation efficiency decreased in the order of citrate-capped nanoparticles > PVP-capped nanocages ≈ CTAC-capped nanoparticles » CTAB-capped nanorods, where PVP, CTAC, and CTAB stand for poly(vinyl pyrrolidone), cetyltrimethylammonium chloride, and cetyltrimethylammonium bromide, resp.
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    73. 73
      Miller, I.; Min, M.; Yang, C.; Tian, C.; Gookin, S.; Carter, D.; Spencer, S. L. Ki67 Is a Graded Rather than a Binary Marker of Proliferation versus Quiescence. Cell Rep. 2018, 24 (5), 1105– 1112,  DOI: 10.1016/j.celrep.2018.06.110
      73
      Ki67 is a Graded Rather than a Binary Marker of Proliferation versus Quiescence
      Miller, Iain; Min, Mingwei; Yang, Chen; Tian, Chengzhe; Gookin, Sara; Carter, Dylan; Spencer, Sabrina L.
      Cell Reports (2018), 24 (5), 1105-1112.e5CODEN: CREED8; ISSN:2211-1247. (Cell Press)
      Ki67 staining is widely used as a proliferation indicator in the clinic, despite poor understanding of this protein's function or dynamics. Here, we track Ki67 levels under endogenous control in single cells over time and find that Ki67 accumulation occurs only during S, G2, and M phases. Ki67 is degraded continuously in G1 and G0 phases, regardless of the cause of entry into G0/quiescence. Consequently, the level of Ki67 during G0 and G1 in individual cells is highly heterogeneous and depends on how long an individual cell has spent in G0. Thus, Ki67 is a graded rather than a binary marker both for cell-cycle progression and time since entry into quiescence.
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    74. 74
      Nguyen, T. N.; Chebbi, I.; Le Fèvre, R.; Guyot, F.; Alphandéry, E. Non-Pyrogenic Highly Pure Magnetosomes for Efficient Hyperthermia Treatment of Prostate Cancer. Appl. Microbiol. Biotechnol. 2023, 107 (4), 1159– 1176,  DOI: 10.1007/s00253-022-12247-9
      74
      Non-pyrogenic highly pure magnetosomes for efficient hyperthermia treatment of prostate cancer
      Nguyen, Tieu Ngoc; Chebbi, Imene; Le Fevre, Raphael; Guyot, Francois; Alphandery, Edouard
      Applied Microbiology and Biotechnology (2023), 107 (4), 1159-1176CODEN: AMBIDG; ISSN:0175-7598. (Springer International Publishing AG)
      We report the fabrication of highly pure magnetosomes that are synthesized by magnetotactic bacteria (MTB) using pharmaceutically compatible growth media, i.e., without compds. of animal origin (yeast exts.), carcinogenic, mutagenic, or toxic for reprodn. (CMR) products, and other heavy metals than iron. To enable magnetosome medical applications, these growth media are reduced and amended compared with media commonly used to grow these bacteria. Furthermore, magnetosomes are made non-pyrogenic by being extd. from these micro-organisms and heated above 400°C to remove and denature bacterial org. material and produce inorg. magnetosome minerals. To be stabilized, these minerals are further coated with citric acid to yield M-CA, leading to fully reconstructed chains of magnetosomes. The heating properties and anti-tumor activity of highly pure M-CA are then studied by bringing M-CA into contact with PC3-Luc tumor cells and by exposing such assembly to an alternating magnetic field (AMF) of 42 mT and 195 kHz during 30 min. While in the absence of AMF, M-CA are obsd. to be non-cytotoxic, they result in a 35% decrease in cell viability following AMF application. The treatment efficacy can be assocd. with a specific absorption rate (SAR) value of M-CA, which is relatively high in cellular environment, i.e., SARcell = 253 ± 11 W/gFe, while being lower than the M-CA SAR value measured in water, i.e., SARwater = 1025 ± 194 W/gFe, highlighting that a redn. in the Brownian contribution to the SAR value in cellular environment does not prevent efficient tumor cell destruction with these nanoparticles.
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    75. 75
      Calatayud, M. P.; Soler, E.; Torres, T. E.; Campos-Gonzalez, E.; Junquera, C.; Ibarra, M. R.; Goya, G. F. Cell Damage Produced by Magnetic Fluid Hyperthermia on Microglial BV2 Cells. Sci. Rep. 2017, 7 (1), 1– 16,  DOI: 10.1038/s41598-017-09059-7
      75
      Butyrate-producing bacteria supplemented in vitro to Crohn's disease patient microbiota increased butyrate production and enhanced intestinal epithelial barrier integrity
      Geirnaert, Annelies; Calatayud, Marta; Grootaert, Charlotte; Laukens, Debby; Devriese, Sarah; Smagghe, Guy; De Vos, Martine; Boon, Nico; Van de Wiele, Tom
      Scientific Reports (2017), 7 (1), 1-14CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
      The management of the dysbiosed gut microbiota in inflammatory bowel diseases (IBD) is gaining more attention as a novel target to control this disease. Probiotic treatment with butyrate-producing bacteria has therapeutic potential since these bacteria are depleted in IBD patients and butyrate has beneficial effects on epithelial barrier function and overall gut health. However, studies assessing the effect of probiotic supplementation on microbe-microbe and host-microbe interactions are rare. In this study, butyrate-producing bacteria (three mono-species and one multispecies mix) were supplemented to the fecal microbial communities of ten Crohn's disease (CD) patients in an in vitro system simulating the mucus- and lumen-assocd. microbiota. Effects of supplementation in short-chain fatty acid levels, bacterial colonization of mucus environment and intestinal epithelial barrier function were evaluated. Treatment with F. prausnitzii and the mix of six butyrate-producers significantly increased the butyrate prodn. by 5-11 mol%, and colonization capacity in mucus- and lumen-assocd. CD microbiota. Treatments with B. pullicaecorum 25-3T and the mix of six butyrate-producers improved epithelial barrier integrity in vitro. This study provides proof-of-concept data for the therapeutic potential of butyrate-producing bacteria in CD and supports the future preclin. development of a probiotic product contg. butyrate-producing species.
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    76. 76
      Crezee, J.; Franken, N. A. P.; Oei, A. L. Hyperthermia-Based Anti-Cancer Treatments. Cancers 2021, 13, 1240,  DOI: 10.3390/cancers13061240
      There is no corresponding record for this reference.
    77. 77
      Sabirzhanov, B.; Stoica, B. A.; Hanscom, M.; Piao, C. S.; Faden, A. I. Over-Expression of HSP70 Attenuates Caspase-Dependent and Caspase-Independent Pathways and Inhibits Neuronal Apoptosis. J. Neurochem. 2012, 123 (4), 542– 554,  DOI: 10.1111/j.1471-4159.2012.07927.x
      77
      Over-expression of HSP70 attenuates caspase-dependent and caspase-independent pathways and inhibits neuronal apoptosis
      Sabirzhanov, Boris; Stoica, Bogdan A.; Hanscom, Marie; Piao, Chun-Shu; Faden, Alan I.
      Journal of Neurochemistry (2012), 123 (3&4), 542-554CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)
      HSP70 is a member of the family of heat-shock proteins that are known to be up-regulated in neurons following injury and/or stress. HSP70 over-expression has been linked to neuroprotection in multiple models, including neurodegenerative disorders. In contrast, less is known about the neuroprotective effects of HSP70 in neuronal apoptosis and with regard to modulation of programmed cell death (PCD) mechanisms in neurons. The authors examd. the effects of HSP70 over-expression by transfection with HSP70-expression plasmids in primary cortical neurons and the SH-SY5Y neuronal cell line using four independent models of apoptosis: etoposide, staurosporine, C2-ceramide, and β-Amyloid. In these apoptotic models, neurons transfected with the HSP70 construct showed significantly reduced induction of nuclear apoptotic markers and/or cell death. Furthermore, the authors demonstrated that HSP70 binds and potentially inactivates Apoptotic protease-activating factor 1, as well as apoptosis-inducing factor, key mols. involved in development of caspase-dependent and caspase-independent PCD, resp. Markers of caspase-dependent PCD, including active caspase-3, caspase-9, and cleaved PARP were attenuated in neurons over-expressing HSP70. These data indicate that HSP70 protects against neuronal apoptosis and suggest that these effects reflect, at least in part, to inhibition of both caspase-dependent and caspase-independent PCD pathways.
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    78. 78
      Calderwood, S. K.; Gong, J. Heat Shock Proteins Promote Cancer: It’s a Protection Racket. Trends Biochem. Sci. 2016, 41 (4), 311– 323,  DOI: 10.1016/j.tibs.2016.01.003
      78
      Heat Shock Proteins Promote Cancer: It's a Protection Racket
      Calderwood, Stuart K.; Gong, Jianlin
      Trends in Biochemical Sciences (2016), 41 (4), 311-323CODEN: TBSCDB; ISSN:0968-0004. (Elsevier Ltd.)
      Heat shock proteins (HSP) are expressed at high levels in cancer and form a fostering environment that is essential for tumor development. Here, we review the recent data in this area, concg. mainly on Hsp27, Hsp70, and Hsp90. The overriding role of HSPs in cancer is to stabilize the active functions of overexpressed and mutated cancer genes. Thus, elevated HSPs are required for many of the traits that underlie the morbidity of cancer, including increased growth, survival, and formation of secondary cancers. In addn., HSPs participate in the evolution of cancer treatment resistance. HSPs are also released from cancer cells and influence malignant properties by receptor-mediated signaling. Current data strongly support efforts to target HSPs in cancer treatment.
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    79. 79
      Moulin, M.; Arrigo, A. P. Caspases Activation in Hyperthermia-Induced Stimulation of TRAIL Apoptosis. Cell Stress Chaperones 2008, 13 (3), 313– 326,  DOI: 10.1007/s12192-008-0027-3
      79
      Caspases activation in hyperthermia-induced stimulation of TRAIL apoptosis
      Moulin, Maryline; Arrigo, Andre-Patrick
      Cell Stress & Chaperones (2008), 13 (3), 313-326CODEN: CSCHFG; ISSN:1355-8145. (Springer)
      In leukemia cells, hyperthermia enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. The phenomenon is caspase-dependent and results in membrane changes leading to an increased recognition of TRAIL death receptors by TRAIL. Because either caspase-2 or an apical proteolytic event has been recently proposed to act as an initiator of the cell death mechanism induced by heat shock, we have investigated the hierarchy of caspase activation in cells exposed to the combined heat shock plus TRAIL treatment. We report here that caspases-2, -3, and -8 were the first caspases to be activated. As expected, caspase-8 is required and indispensable during the initiation of this death signaling. Caspase-2 may also participate in the phenomenon but, in contrast to caspase-8, its presence appears dispensable because its depletion by small interfering RNA is devoid of effects. Our observations also suggest a role of caspase-3 and of a particular cleaved form of this caspase during the early signals of heat shock plus TRAIL-induced apoptosis.
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    80. 80
      Court, K. A.; Hatakeyama, H.; Wu, S. Y.; Lingegowda, M. S.; Rodríguez-Aguayo, C.; López-Berestein, G.; Ju-Seog, L.; Rinaldi, C.; Juan, E. J.; Sood, A. K.; Torres-Lugo, M. HSP70 Inhibition Synergistically Enhances the Effects of Magnetic Fluid Hyperthermia in Ovarian Cancer. Mol. Cancer Ther. 2017, 16 (5), 966– 976,  DOI: 10.1158/1535-7163.MCT-16-0519
      80
      HSP70 Inhibition Synergistically Enhances the Effects of Magnetic Fluid Hyperthermia in Ovarian Cancer
      Court, Karem A.; Hatakeyama, Hiroto; Wu, Sherry Y.; Lingegowda, Mangala S.; Rodriguez-Aguayo, Cristian; Liopez-Berestein, Gabriel; Lee, Ju-Seog; Rinaldi, Carlos; Juan, Eduardo J.; Sood, Anil K.; Torres-Lugo, Madeline
      Molecular Cancer Therapeutics (2017), 16 (5), 966-976CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)
      Hyperthermia has been investigated as a potential treatment for cancer. However, specificity in hyperthermia application remains a significant challenge. Magnetic fluid hyperthermia (MFH) may be an alternative to surpass such a challenge, but implications of MFH at the cellular level are not well understood. Therefore, the present work focused on the examn. of gene expression after MFH treatment and using such information to identify target genes that when inhibited could produce an enhanced therapeutic outcome after MFH. Genomic analyzes were performed using ovarian cancer cells exposed to MFH for 30 min at 43°C, which revealed that heat shock protein (HSP) genes, including HSPA6, were upregulated. HSPA6 encodes the Hsp70, and its expression was confirmed by PCR in HeyA8 and A2780cp20 ovarian cancer cells. Two strategies were investigated to inhibit Hsp70-related genes, siRNA and Hsp70 protein function inhibition by 2-phenylethyenesulfonamide (PES). Both strategies resulted in decreased cell viability following exposure to MFH. Combination index was calcd. for PES treatment reporting a synergistic effect. In vivo efficacy expts. with HSPA6 siRNA and MFH were performed using the A2780cp20 and HeyA8 ovarian cancer mouse models. A significantly redn. in tumor growth rate was obsd. with combination therapy. PES and MFH efficacy were also evaluated in the HeyA8 i.p. tumor model, and resulted in robust antitumor effects. This work demonstrated that HSP70 inhibition combination with MFH generate a synergistic effect and could be a promising target to enhance MFH therapeutic outcomes in ovarian cancer. Mol Cancer Ther; 16(5); 966-76. 2017 AACR.
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    81. 81
      Şen, D.; Emanet, M.; Ciofani, G. Nanotechnology-Based Strategies to Evaluate and Counteract Cancer Metastasis and Neoangiogenesis. Adv. Healthc. Mater. 2021, 10 (10), 1– 30,  DOI: 10.1002/adhm.202002163
      There is no corresponding record for this reference.
    82. 82
      Soenen, S. J. H.; Himmelreich, U.; Nuytten, N.; De Cuyper, M. Cytotoxic Effects of Iron Oxide Nanoparticles and Implications for Safety in Cell Labelling. Biomaterials 2011, 32 (1), 195– 205,  DOI: 10.1016/j.biomaterials.2010.08.075
      82
      Cytotoxic effects of iron oxide nanoparticles and implications for safety in cell labelling
      Soenen Stefaan J H; Himmelreich Uwe; Nuytten Nele; De Cuyper Marcel
      Biomaterials (2011), 32 (1), 195-205 ISSN:.
      The in vitro labelling of cultured cells with iron oxide nanoparticles (NPs) is a frequent practice in biomedical research. To date, the potential cytotoxicity of these particles remains an issue of debate. In the present study, 4 different NP types (dextran-coated Endorem, carboxydextran-coated Resovist, lipid-coated magnetoliposomes (MLs) and citrate-coated very small iron oxide particles (VSOP)) are tested on a variety of cell types, being C17.2 neural progenitor cells, PC12 rat pheochromocytoma cells and human blood outgrowth endothelial cells. Using different NP concentrations, the effect of the NPs on cell morphology, cytoskeleton, proliferation, reactive oxygen species, functionality, viability and cellular homeostasis is investigated. Through a systematic study, the safe concentrations for every particle type are determined, showing that MLs can lead up to 67.37 ± 5.98 pg Fe/cell whereas VSOP are the most toxic particles and only reach 18.65 ± 2.07 pg Fe/cell. Using these concentrations, it is shown that for MRI up to 500 cells/μl labelled with VSOP are required to efficiently visualize in an agar phantom in contrast to only 50 cells/μl for MLs and 200 cells/μl for Endorem and Resovist. These results highlight the importance of in-depth cytotoxic evaluation of cell labelling studies as at non-toxic concentrations, some particles appear to be less suitable for the MR visualization of labelled cells.
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    83. 83
      Mulens-Arias, V.; Rojas, J. M.; Sanz-ortega, L.; Portilla, Y.; Pérez-yagüe, S.; Barber, D. F. Polyethylenimine-Coated Superparamagnetic Iron Oxide Nanoparticles Impair in vitro and in vivo Angiogenesis ☆,☆☆,☆☆☆. Nanomedicine Nanotechnology, Biol. Med. 2019, 21, 102063,  DOI: 10.1016/j.nano.2019.102063
      83
      Polyethylenimine-coated superparamagnetic iron oxide nanoparticles impair in vitro and in vivo angiogenesis
      Mulens-Arias Vladimir; Rojas Jose Manuel; Sanz-Ortega Laura; Portilla Yadileiny; Perez-Yague Sonia; Barber Domingo F
      Nanomedicine : nanotechnology, biology, and medicine (2019), 21 (), 102063 ISSN:.
      Endothelial cells are essential to tumor vascularization and impairing their activity can potentially limit tumor growth. Since polyethylenimine (PEI)-coated superparamagnetic iron oxide nanoparticles (SPIONs) are bioactive nanosystems that modulate inflammatory macrophage responses and limit tumor cell invasion, we evaluated their effects on endothelial cell angiogenesis. PEI-SPION triggered proinflammatory gene profiles in a murine endothelial cell line and in primary human umbilical cord vein endothelial cells (HUVECs). These nanoparticles impaired endothelial cell migration and inhibited HUVEC tube formation. Magnetically tumor-targeted PEI-SPIONs reduced tumor vessel numbers and promoted intratumor macrophage infiltration in a tumor xenograft model. PEI-SPION treatment impaired M2 macrophage-promoted tube formation and affected HUVEC cytoskeleton by limiting Src and Cortactin activation. These mechanisms could contribute to PEI-SPION in vitro and in vivo antiangiogenic potential. These data confirm that PEI-SPION administration and application of a localized magnetic field could offer an affordable anti-angiogenic anti-tumoral targeted treatment that would complement other therapies.
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    84. 84
      Wu, V. M.; Huynh, E.; Tang, S.; Uskoković, V. Brain and Bone Cancer Targeting by a Ferrofluid Composed of Superparamagnetic Iron-Oxide/Silica/Carbon Nanoparticles (Earthicles). Acta Biomater. 2019, 88, 422– 447,  DOI: 10.1016/j.actbio.2019.01.064
      84
      Brain and bone cancer targeting by a ferrofluid composed of superparamagnetic iron-oxide/silica/carbon nanoparticles (earthicles)
      Wu, Victoria M.; Huynh, Eric; Tang, Sean; Uskokovic, Vuk
      Acta Biomaterialia (2019), 88 (), 422-447CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)
      Nanoparticles were synthesized hydrothermally and characterized using range of spectroscopic, diffractometric, hydrodynamic and electron microscopy techniques. Double coating on SPIONs affected no. of physicochem. and biol. properties, including colloidal stability and cancer targeting efficacy. Nanoparticles decreased viability of glioblastoma and osteosarcoma cells and tumors more than that of their primary and non-transformed analogs. They showed greater preference for cancer cells because of higher rate of uptake by these cells and pronounced adherence to cancer cell membrane. Even in ultralow alternate magnetic field, nanoparticles generated sufficient heat to cause tumor death. Nanoparticles in MDCK-MDR1 BBB model caused mislocalization of claudin-1 at tight junctions, underexpression of ZO-1 and no effect on occludin-1 and transepithelial resistance. Nanoparticles were detected in basolateral compartments and examn. of LAMP1 demonstrated that nanoparticles escaped lysosome, traversed BBB transcellularly and localized to optic lobes of third instar larval brains of D. melanogaster. Passage was noninvasive and caused no adverse systemic effects to animals. These nanoparticulate ferrofluids preferentially bind to cancer cells and, hence, exhibit greater toxicity in these cells compared to primary cells. They are also effective against solid tumors in vitro, can cross BBB in Drosophila, and are nontoxic based on developmental studies of flies raised in ferrofluid-infused media.
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    85. 85
      Hildebrandt, B.; Wust, P.; Ahlers, O.; Dieing, A.; Sreenivasa, G.; Kerner, T.; Felix, R.; Riess, H. The Cellular and Molecular Basis of Hyperthermia. Crit. Rev. Oncol. Hematol. 2002, 43 (1), 33– 56,  DOI: 10.1016/S1040-8428(01)00179-2
      85
      The cellular and molecular basis of hyperthermia
      Hildebrandt Bert; Wust Peter; Ahlers Olaf; Dieing Annette; Sreenivasa Geetha; Kerner Thoralf; Felix Roland; Riess Hanno
      Critical reviews in oncology/hematology (2002), 43 (1), 33-56 ISSN:1040-8428.
      In oncology, the term 'hyperthermia' refers to the treatment of malignant diseases by administering heat in various ways. Hyperthermia is usually applied as an adjunct to an already established treatment modality (especially radiotherapy and chemotherapy), where tumor temperatures in the range of 40-43 degrees C are aspired. In several clinical phase-III trials, an improvement of both local control and survival rates have been demonstrated by adding local/regional hyperthermia to radiotherapy in patients with locally advanced or recurrent superficial and pelvic tumors. In addition, interstitial hyperthermia, hyperthermic chemoperfusion, and whole-body hyperthermia (WBH) are under clinical investigation, and some positive comparative trials have already been completed. In parallel to clinical research, several aspects of heat action have been examined in numerous pre-clinical studies since the 1970s. However, an unequivocal identification of the mechanisms leading to favorable clinical results of hyperthermia have not yet been identified for various reasons. This manuscript deals with discussions concerning the direct cytotoxic effect of heat, heat-induced alterations of the tumor microenvironment, synergism of heat in conjunction with radiation and drugs, as well as, the presumed cellular effects of hyperthermia including the expression of heat-shock proteins (HSP), induction and regulation of apoptosis, signal transduction, and modulation of drug resistance by hyperthermia.
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    86. 86
      Jordan, A.; Scholz, R.; Maier-Hauff, K.; Johannsen, M.; Wust, P.; Nadobny, J.; Schirra, H.; Schmi