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Self-Therapeutic Nanomaterials for Cancer Therapy: A Review

  • Muhammad Adeel*
    Muhammad Adeel
    PhD School in Science and Technology of Bio and Nanomaterials, Ca’ Foscari University of Venice, Venice 30170, Italy
    Department of Molecular Sciences and Nanosystems, Ca’ Foscari University of Venice, Venice 30170, Italy
    Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano 33081, Italy
    *Email: [email protected]. Phone: (+39)0412348910. Fax: (+39)0434659370 (M.A.).
    More by Muhammad Adeel
    Orcidhttp://orcid.org/0000-0003-0916-4151
  • , 
  • Fahriye Duzagac
    Fahriye Duzagac
    Department of Molecular Sciences and Nanosystems, Ca’ Foscari University of Venice, Venice 30170, Italy
    More by Fahriye Duzagac
    Orcidhttp://orcid.org/0000-0002-4130-2246
  • , 
  • Vincenzo Canzonieri
    Vincenzo Canzonieri
    Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano 33081, Italy
    Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste 34127, Italy
    More by Vincenzo Canzonieri
    Orcidhttp://orcid.org/0000-0001-6010-0976
  • , and 
  • Flavio Rizzolio*
    Flavio Rizzolio
    Department of Molecular Sciences and Nanosystems, Ca’ Foscari University of Venice, Venice 30170, Italy
    Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano 33081, Italy
    *Email: [email protected] Phone: (+39)0412348910 Fax: (+39)0434659370 (F.R.).
    More by Flavio Rizzolio
    Orcidhttp://orcid.org/0000-0002-3400-4363
Cite this: ACS Appl. Nano Mater. 2020, 3, 6, 4962–4971
Publication Date (Web):June 3, 2020
https://doi.org/10.1021/acsanm.0c00762

Copyright © 2022 The Authors. Published by American Chemical Society. This publication is licensed under

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Abstract

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Cancer is a commonly lethal disease that causes many deaths every year around the world. Many strategies have been applied to treat cancer, such as surgery, radiation, and chemotherapy, but all of these therapeutic approaches are limited. Nanotechnology could provide a tremendous platform to boost the efficacy of therapeutic systems from the bench to clinical applications. The current trend of using nanomaterials for therapeutic applications is limited to drug delivery and external stimuli-responsive systems. However, several nanomaterials can reduce the growth of aggressive tumors through their self-therapeutic properties. In this review, we discuss the self-therapeutic nanomaterials that can kill cancer cells without the need for any external stimulation (heat, light, radiation, or a magnetic field) or the loading of any extra therapeutic compounds. These nanomaterials can produce reactive oxygen species, act as deoxygenating agents, or produce free radicals at tumor sites. Self-therapeutic peptide-based and other organic nanomaterials that are used to inhibit multidrug resistance (MDR) proteins, e.g., P-glycoprotein (P-gp), are also discussed. This review discusses the possible mechanisms of action of self-therapeutic nanomaterials for cancer inhibition, highlighting critical and future aspects.

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1. Introduction

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Cancer is the second most common cause of death around the globe. It killed 9.6 million people in 2018. According to the WHO, one in five men and one in six women will develop cancer in their life and one in eight men and one in 11 women will die from this serious disease. (1) Several methods have been developed for treatment, but there are still no available approaches that can completely eradicate this life-threatening disease. Cancer therapy is currently mostly limited to surgery, radiation, and chemotherapy, but they each have several disadvantages and often fail to cure the condition. (2)
Recently, nanomaterials have attracted much attention from scientists interested in cancer therapy because of their versatile physical and chemical properties. (3) Many reports have focused on the use of nanomaterials as carriers of therapeutic compounds. These therapeutic systems have been extended by introducing external stimuli (e.g., light, magnetic waves and heat) to improve drug release at the tumor sites. These approaches can be further subdivided into photodynamic, photothermal, magnetic, and neutron-capturing systems. Unfortunately, the use of nanomaterials as carriers of therapeutic compounds has some flaws, which preclude these therapeutic systems from clinical applications. The major challenges are a low drug loading efficiency, low solubility in an aqueous media, poor ability to cross in vivo barriers and penetrate inside the tumor (less than 1% reach the tumor), problematic physical and chemical interactions of hydrophobic therapeutic compounds with nanomaterials, in vivo instability, a suboptimal biodistribution, low tumor targeting ability, and a suboptimal drug release profile. (4) To minimize all of these issues and bring nanomaterials from the bench to clinics, scientists are trying to develop optimized self-therapeutic nanomaterials that can work like a “magic nano bullet” without the loading of additional therapeutic compounds or external stimuli dependency to make these systems practical for clinical applications.
Most of the organic nanoparticles (liposomes, micelles, exosomes, lipids, PLA, PLGA), (5) inorganic nanoparticles (gold, silver, silica, iron, graphene, carbon quantum dots), and composites (metal–organic frameworks (MOF), transition metals dichalcogenide (TMD)) were designed as carriers in drug-delivery systems (6) or for use in external stimuli-based systems such as photodynamic therapy (PDT), (7) photothermal therapy (PTT), (8) magnetic therapy, (9) and boron neutron-capturing therapy (BNCP). (10) All of these external dependencies and low loading efficiency of therapeutic compounds are shortcomings, which has led to the failure of these systems at the clinical level. Additionally, these therapeutic systems need specific special equipment that is difficult to use and requires confining the patient in the hospital.
In this review, we will go over the available data on nanotherapeutic systems derived directly from nanomaterials through some specific mechanisms (using the intrinsic properties of the materials) and discuss the possible future uses of these systems.

2. Direct Cancer Therapy Driven by Nanomaterials

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The application of nanotechnology to cancer therapy could extend beyond drug delivery into the creation of new therapeutics able to destroy the tumors with minimal damage to healthy tissues and organs, as well as the detection and elimination of cancer cells during the initial stage of tumorigenesis. These relatively small particles can also be functionalized with ligands, nucleic acids, peptides or antibodies that bind to specific target molecules. Because of certain intrinsic properties of nanomaterials (reaction with oxygen species, heat and hazardous gas producers) and biocompatibilities, they are quite interesting to use directly for therapeutic purposes. Herein, we summarized self-therapeutic nanomaterials that were successfully used to target and eradicate cancer cells along with their possible mechanism of action in cancer treatment.

Metalloid Boron as an Enzyme Inhibitor

Neutron-capturing therapy is usually done with compounds containing boron. Locher was the first to report on the biological effects and therapeutic possibilities of boron neutron-capturing therapy (BNCT). (11) BNCT is based on nuclear capture and fusion reactions when nonirradiated boron-10 (B10) is irradiated with low energy neutrons to form 4He+7Li+ fusion energy (E). The reaction mechanism is presented below:
These nuclei produced closely spaced ionizations (the production of alpha particles and heat) of a path length of approximately one cell dimension (5–7 μm) that is used to destroy cancer cells. (12) The neutron-capturing property is limited only to boron-containing cells and external neutron radiation bombardment. (13) Several boron therapeutic compounds such as sodium borocaptate and boronophenylalanine are in clinical trials for neutron-targeted therapy, (13) but there is still a need for external stimuli by neutron bombardment to produce 4He+7Li+E.
In the literature, there are some reports in which boron-based compounds were directly used for the growth inhibition of different cancer cells. The biological roles of boron include the regulation of gene expression, growth, and proliferation. (14) Boron is used in synthetic chemistry because of its unique characteristics that allows it to form a covalent bond with carbon. Mostly, trivalent boron reagents are electrophiles and when they get a pair of electrons from nucleophiles, they adopt a tetrahedral configuration (sp3) to satisfy the octet rule. Generally, the conversion of sp2 carbonyl carbon to sp3 tetrahedral carbon inhibits the activity of enzymes. Therefore, the substitution of carbon by boron is a good transition state analogy for the suppression of hydrolytic enzymes. Additionally, boron has a strong affinity for oxygen-forming borates that are involved in the inhibition of enzymes. (15)
Bortezomib is an FDA-approved drug for treating multiple myeloma and mantle cell lymphoma. (16) The clinical development of bortezomib (trade name Velcade) occurred after the discovery of the ability of boron to reversibly inhibit the proteolytic/chymotryptic activity of the 26S proteasome subunit in mammalian cells. (17) Suppression of the intracellular protein degradation pathway (proteasomes) changes the levels of multiple intracellular signaling and regulatory proteins in addition to altering the regulation of cellular processes that can lead to growth arrest or apoptosis. In vitro studies showed that bortezomib is oxidatively metabolized primarily through multiple cytochrome P450 enzymes. The main metabolic pathway is deboronation to create two metabolites that are hydroxylated to inactive metabolites. (18)
Recently, boron compounds have gained interest as protective and therapeutic agents for prostate cancer and other cancers. (19−22) Boric acid (BA), the predominant form of boron in plasma, shows boron-mediated anticancer mechanisms in prostate cancer by reducing intracellular calcium signals and calcium storage, decreasing enzymatic activities (serine protease, NAD-dehydrogenases, etc.) and finally inhibiting cancer cell proliferation. (23)
In 2004, Barranco et al. used boric acid for the treatment of human prostate cancer cells. (14) Boron depleted media was prepared by its treatment with boron specific ion-exchange resin, which was added to the supplemented media of the DU-145 and LNCaP prostate cancer cell lines. The growth of the cancer cell lines were inhibited in a dose-dependent manner. For nontumorigenic cells, the required dose to inhibit growth was much higher. (14)
Recently, an interesting report was published by Ciofani et al. about the synthesis of hexagonal boron nitride nanoparticles for prostate cancer therapy. The authors synthesized hexagonal boron nitride nanoparticles by a tube furnace method at a high temperature (1300 °C) while using boric acid and ammonia as precursors for boron and nitrogen sources, respectively. (24) The synthesized hexagonal boron nitride nanomaterials were degradable in an aqueous media and showed a high cellular internalization profile. The mechanism of action was explained by the production of reactive oxygen species (ROS), which results in damage to membrane lipids, protein, and DNA as critical cell components, and mitochondrial dysfunction, which activates the apoptotic processes.
In 2014, Li et al. prepared hollow boron nitride nanospheres (BNs) as a boron source for prostate cancer therapy. The authors synthesized the BNs by a traditional chemical vapor deposition (CVD) method. After the CVD reaction, the precursor of BN was collected and further heated at different temperatures (900, 1025, and 1400 °C) in an argon (Ar) atmosphere to improve its crystallinity and allow for controlled boron release. The authors examined two key damage-associated pattern protein markers: caspase-3/7 to evaluate apoptosis and lactate dehydrogenase (LDH) release to evaluate necrosis. The results indicated that apoptosis and necrosis are enhanced by BN spheres compared to boric acid in vitro. The authors also investigated the in vivo anticancer effectiveness of BA and hollow BNs in subcutaneously and orthotopically injected LNCap prostate cancer cell mouse models. It was shown that BNs and BA significantly suppressed prostate tumor growth compared with the control (Figure 1). (23) Besides, taking advantage of the hollow shape of the BNs and their maximum surface to volume ratio, paclitaxel was loaded successfully to simultaneously use the system as a traditional drug-delivery system. Significant tumor inhibition was observed with BNs loaded with paclitaxel in both in vitro and in vivo experiments.

Figure 1

Figure 1. In vitro and in vivo effects of boron nitride nanospheres (BNs). (a) Different levels of necrosis (LDH) and apoptosis (caspase 3/7) in prostate cancer cells due to the release of boron from BA or hollow BN spheres. (b) BNS, BA, and saline effects on LNCap mouse tumor models. (c) Effect of different formulations of boron on the inhibition of tumor growth and (d) tumor volume in mice models. Reproduced with permission from ref (23). Copyright 2017 Springer Nature.

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Boron compounds can also be effectively used in Prostate-Specific Antigen (PSA) mediated tumor growth. PSA is a serine protease and is one of the most abundant proteins secreted with chymotrypsin-like activity in human prostate epithelium and it is a well-established marker of prostate cancer. (25) PSA is thought to cleave insulin-like growth factor-binding protein-3 (IGFBP-3) and lead to tumor growth by increasing local IGF-1 levels and its mitogenic capabilities. (26) Gallardo-Williams et al. used boron supplementation to inhibit the growth and local expression of IGF-1 in human prostate adenocarcinoma cells (LNCaP) implanted in nude mice. (25) Moreover, boron-enriched diets result in inhibition of different kinds of cancers such as lung, prostate, and cervical cancers because of boron’s role in a variety of enzymatic inhibitions such as serine proteases, NAD-dehydrogenases, and mRNA splicing, as well as receptor binding mimicry and the induction of apoptosis. (21) All of these findings together have opened up a new way to cure cancer by synthesizing biocompatible self-therapeutic boron-based nanomaterials.
The common concept in all of these reports is that the arrest of cancer growth is mediated by boron atoms. Many boron-based nanomaterials such as boron nitride nanosheets, nanotubes, nanoparticles, and rare earth boride nanostructures have been synthesized by several different methods such as CVD, hydrothermal methods and electrochemical methods. (27) Boric acid and boron nitride are the most abundant forms and could be a good source of boron atoms for therapeutic applications. Because they are highly soluble in biological fluids, (23) nanomaterials with a certain crystallinity as a boron source would be a good choice for therapeutic applications. Mateti et al. synthesized different types of boron nitride nanomaterials and tested Saos-2 osteoblast-like cells for compatibility tests. (28) The authors claim that biocompatibility strongly depends on their size, shape, structure, and surface chemical properties and that cell death is caused by the unsaturated boron atoms located at the nanosheets edge or on the particle surface. Therefore, for therapeutic applications, boron-based nanomaterials should have a structure and chemical and surface properties where plenty of unsaturated boron atoms are present. The structure should be not too amorphous because boron atoms will dissolve in biological fluids before reaching the tumor sites, and not too stable since it needs to be biodegradable and provide enough boron to arrest the tumor growth, regardless of any method of synthesis. Additionally, the replacement of other atoms such as carbon with boron could be another choice to inhibit cancer-related enzymes as previously discussed.

Oxygen-Capturing Approach

Though it is obvious, the primary tumor or metastasis can grow to a size of about 1–2 mm3 if provided a sufficient supply of oxygen and nutrients by diffusion, but tumor growth beyond this size requires vascularization, a process called angiogenesis. (29) When tumors switch to an angiogenic phenotype, which refers to a phenotypic change in an early stage of tumor development necessary for growth beyond 2–3 mm in size, an angiogenic switch is triggered and attracts the growth of blood vessels. (30)
Angiogenesis is controlled by the upregulation of stimulators and the downregulation of inhibitors, which could trigger the angiogenic transduction pathway, which plays a pivotal role in tumor growth, progression, and metastasis of cancer. (31) Antiangiogenic strategies alone might not be effective enough to eradicate tumors due to the excessive compensatory mechanisms by which blood vessels will be remodeled. (32,33) Most antiangiogenic small molecule drugs cause toxicity and require the development of new strategies in a suitable delivery system. (34) Moreover, abnormal or leaky tumor vasculature during tumor angiogenesis results in poor delivery of angiogenic inhibitors, exhibiting a poor pharmacokinetic profile within the tumor stroma. In this respect, nanomedicine plays a crucial role. (35) Because of the small size and high surface volume ratio of nanotheranostic-based antitumor agents, they can be used to more effectively target tumor endothelial cells. (36) In this scenario, several investigators demonstrated novel nanotechnology-based diagnostic and therapeutic approaches for the treatment of cancer. Mukherjee and Patra provided some examples of new nanomaterials including copper, carbon, silver, gold, silica, chitosan, and peptides conjugated with antiangiogenic properties. (37) The limits of these approaches are their dependence from external drugs and stimuli and the accumulation of toxic metals or byproducts in the human body. To overcome these hurdles, Zhang et al. developed nanomaterials that can not only stop the growth of unwanted blood vessels by blocking them with their soluble byproducts but could also deprive tumor cells of oxygen, resulting in the inhibition of tumor growth. (38) It was also reported that magnesium silicide nanoparticles (MS NPS) could be used as deoxygenation agents for cancer therapy (Figure 2). (38)

Figure 2

Figure 2. A schematic illustration of intratumoral deoxygenation utilizing magnesium silicide nanoparticles (MS NPS): Reproduced with permission from ref (38). Copyright 2017 Springer Nature.

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In this report, the authors synthesized injectable MS NPs by self-propagating high-temperature synthesis in an O2/Ar mixed-gas atmosphere. The excess of O2 exothermally reacted with the excess of Mg followed by a subsequent combination reaction between Mg and Si, yielding Mg2Si/MgO mixed particles with a core–shell morphology (Mg2Si core within a thin outer MgO shell). The product (Mg2Si/MgO) was purified to obtain Mg2Si and remove the MgO particles (because it could inhibit the unwanted growth of grains) and was further modified with polyvinylpyrrolidone (PVP) to rapidly absorb molecular oxygen from cancer cells by acting as a deoxygenation agent (DOA) and to block tumor capillaries from being reoxygenated. In a mouse model, tumor growth was significantly inhibited. It was claimed that the byproducts (waste) of the nanomaterials were used to cover the blood capillaries that provided oxygen to the tumor. The possible mechanism of action is presented below:
Here, the Mg2Si nanoparticles capture oxygen from the tumor and leave the bioproduct SiO2, which is useful to cover up the ends of unwanted tumor vessels and maintain intratumoral hypoxia without any long-term toxic effects. Hence, synthesizing these kinds of materials with specific properties such as oxygen capture together with the blockage of extra blood vessels by their byproducts could bring about advances in antiangiogenesis therapy.
The synthesis of other biocompatible nanomaterials for use as deoxygenation agents based on SiO2 and manganese-based materials is demanding in the current therapeutic systems. Any technique adopted to synthesize these type of materials as deoxygenation agents is worthwhile provided that the byproducts are biocompatible or safely eliminated from the body and the material (composite) has the ability to absorb certain levels of oxygen from the tumor microenvironment (one mole of material in its composite byproduct form could have the ability to consume two moles of oxygen molecules or even more). (38)

Highly Toxic Hydroxyl Radical Ions for Cancer Cell Death

The Fenton chemical reaction mechanism is utilized in cancer by converting H2O2 (present at a much higher concentration than in normal cells, ranging from 100 μM to 1 mM in the tumoral microenvironment) into highly toxic hydroxyl free radicals (OH·) to efficiently kill cancer cells and suppress tumor growth. (39−43) Several research groups have published the synthesis of different nanomaterials such as Fe2O3, MnFe2O4, (44) FeOx-MSNs, (45) silver, (46) gold, (47) and α-Fe2O3 (48) that take advantage of the Fenton reaction mechanism to kill cancer cells.
Zhang et al. developed amorphous iron nanoparticles (AFeNPs) as cancer theragnostics while taking advantage of overproduced H2O2 in the tumor using the Fenton chemical process. The AFeNPs were synthesized by a hubble-bubble technique where Fe3+ was designed to occur in a bubble film constructed from an amphiphilic block copolymer F-127 (Pluronic). The precursor solution was confined in the small space between the F-127 bilayers to limit the long-range diffusion of iron atoms and to suppress the nucleation and growth of the crystalline phase of FeNPs. The addition of PVP to increase the viscosity and a citrate chelator to decrease the concentration of free iron ions further controlled the formation of FeNPs. Finally, a freeze-drying technique was used to obtain fragments of the bubble film.
The amorphous structure and the ionization of AFeNPs enabled the on-demand release of a ferrous ion into the tumor, which led to the production of an excessive amount of OH· free radicals in the tumor microenvironment. (49) The Fenton chemical reaction with iron ions (Fe2+, Fe3+) in the presence of H2O2 to produce free radicles (OH·) is shown below.
Ranji-Burachaloo et al. synthesized a reduced iron-based metal–organic framework attached to folic acid (rMOF-FA) as a controlled released source of iron in an acidic environment (characteristic of tumor sites). The rMOF-FA was synthesized by a simple hydrothermal method where Pluronic F-127 as a surfactant and ferric chloride (FeCl3·6H2O) as precursor solutions were mixed followed by the addition of acetic acid and the precipitate was transferred into an autoclave. For the reduction of iron-based MOF, it was treated with hydroquinone that was further functionalized with folic acid (FA) by EDC/NH chemistry to obtain rMOF-FA and used for the controlled release of iron in acidic conditions. The released iron reacted with H2O2 in tumor sites to produce OH· ions that further oxidized protein lipids and DNA to decrease cell viability. The in vitro experiments showed that rMOF-FA is highly toxic to cancer cells (HeLa) because of the production of free radicals (OH·), whereas they are much less toxic for normal cells (NIH-3T3) (Figure 3). (39)

Figure 3

Figure 3. Fenton chemical approach to OH· ion therapeutic systems. (a) Schematic illustration of rMOF-FA nanoparticles for cancer therapy. (b) rMOF-FA effects on HeLa and NIH-3T3 cells. (c) Peroxidase-like activity of rMOF-FA nanoparticles. (d) Synthesis scheme of rMOF-FA nanoparticles. Reproduced with permission from ref (39). Copyright 2017 American Chemical Society.

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Because the Fenton mechanism suffers from low-level production of free radicals OH· ions, many research groups have improved this approach by combining it with other therapeutic systems such as sono-fenton, (50) photofenton, (51) photothermal therapy (PTT), and chemotherapy. (52) Several other research groups also proposed different compounds besides iron, which could produce Fenton-like reactions using cations such as Mn2+, Cu1+, Cr4+, and V2+. (53) The overall compound should have the capacity to release cations gently to start a Fenton-like reaction and the material should be biodegradable enough to provide cations in the tumor microenvironment.

Self-Therapeutic Organic Nanomaterials

Organic materials such as peptide-based nanomaterials are used in medicine for therapeutic applications. The major advantage of peptide-based therapeutic systems is that they could target cancer cells with lower toxicity to normal tissues. (54) The (KLAKLAK)2 (KLAK) amphiphilic peptide is a well-known antitumor peptide widely used in cancer therapy in vitro and in vivo that suppresses the growth of aggressive tumors by damaging the membrane of mitochondria. (55) Wang et al. prepared a library of KLAK- based nanomaterials for cancer therapy by in situ polymerization and optimized the nanomaterials with different ratios and components. (56) The beclin1 peptide is another tumor suppressor peptide; however, the in vivo application of this peptide is limited because of its low stability. The stability of this peptide was improved by a supramolecular approach, conjugating poly(β-amino ester)s with the beclin1 peptide (P-Bec1), which significantly enhanced its in vivo stability, extending its circulation time and EPR effect. The (P-Bec1) nanoparticles were tested in MCF-7 breast cancer cells and showed enhanced cytotoxicity and in vivo therapeutic effects. (57)
MDM2 is an E3 ubiquitin ligase that can target p53 for polyubiquitination and proteasomal degradation. (58) For restoring p53 tumor suppression activity, the disruption of interactions between the MDM2 and p53 axis is a promising strategy. PMI, a potent inhibitor of MDM2-p53 interactions, can efficiently activate p53 and the downstream BH3-only family proteins (such as Bim, PUMA, and NOXA) to promote apoptosis by sequestering antiapoptotic Bcl-2 family proteins. However, because of its low proteolytic stability and poor cell-membrane penetration, the tumor-inhibiting activity of PMI is severely limited. (59) Yan et al. suggested combining the BIM peptide, which forms the BH3 domain of the pro-apoptotic Bim protein, with PMI in a nanoplatform-based peptide delivery system to achieve potent antitumor activity. The peptide–lanthanide clustered nanosystems (LDC-PMI-BIM-iNGR) were synthesized through thiol–poly(ethylene glycol)–thiol (SH-PEG-SH) polymer-induced molecular assembly of three peptides (PMI, BIM, and a cyclic peptide iNGR targeted to cancer cells) with biocompatible lanthanide-doped fluorescent nanoparticles (LDN). LDC-PMI-BIM-iNGR were tested in vitro and in vivo and showed lower systemic toxicity and off-target effects than doxorubicin, a commonly used chemotherapeutic agent, achieving a safe and reliable antitumor efficacy (Figure 4). (60)

Figure 4

Figure 4. Schematic diagram of peptide-based nanoclusters and their anticancer activity: (a) Graphical illustration for the construction of lanthanide-doped nanoclusters (LDC) and their cancer cell killing activity. (b) Schematic diagram of the production of small nanoparticles by the disintegration of large size nanocluster in the reducing intracellular environment. Reproduced with the permission of ref (60). Copyright 2018 American Chemical Society.

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Several other self-assembled peptide-based nanomaterials for therapeutic applications have been well summarized by Qi et al. (55) and Wu et al. (54)
MDR is one of the major problems for traditional chemotherapeutic systems and one of its mechanisms is the overexpression of drug efflux pumps, such as P-glycoprotein (P-gp), which expel different agents out of the tumor cells. Several P-gp inhibitors have been developed. Tuguntaev et al. synthesized vitamin E derivatives by combining P-gp inhibitors to overcome MDR. The authors developed a nanomicellar drug-delivery system with a thin-film hydration technique as a carrier for doxorubicin in which d-α-tocopheryl polyethylene glycol 1000 succinate was used as a P-gp inhibitor. The system showed excellent cytotoxicity for in vitro and in vivo experiments. (61) In another report, Dai et al. prepared self-assembling polyethylene glycol-phosphoethanolamine-based copolymers (PEG-pp-PE) as a targeted delivery system and as an inhibitor of P-gp (Figure 5). (62) Kou et al. summarized several other examples of P-gp inhibitory nanomaterials and their applications as drug-delivery systems. (63)

Figure 5

Figure 5. P-gp inhibition by PEG-pp-PE micelles. Reproduced with permission from ref (62). Copyright 2016 American Chemical Society.

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The synthesis of these organic nanomaterials always depends on considering their action to inhibit cancer tumors, e.g., peptide-based nanoclusters are used to enhance their in vivo stability and penetration abilities inside tumors. Similarly, P-gp inhibitors are conjugated to increase their in vivo stability and enhance their cytotoxicity. However, the overall synthesis of the materials should follow the same standards as defined in the literature for any drug-delivery systems such as size, shape, and surface properties, with safe elimination of byproducts.

3. Other Self-Therapeutic Nanomaterials

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In recent years, other reports have been published about the anticancer abilities of nanomaterials and their byproducts. Recently, Li et al. published a report about the biodegradation of graphene-based nanomaterials in blood plasma and their in vitro and in vivo antitumor abilities. After incubating graphene (G) and graphene oxide (GO) in blood plasma at 37 °C for several days, the resulting nanomaterials were tested for their antitumor abilities in in vitro and in vivo experiments. (64) The results showed that the pristine graphene-based materials caused secondary structure damage to proteins and disturbances of cellular metabolic pathways while the bio transformed materials (degraded) were biocompatible and influenced specific organ therapies. The materials were further used as traditional drug-delivery systems by the loading of doxorubicin. The bio-transformed materials exhibited high efficiencies of drug delivery and more pronounced targeting and tumor-killing abilities. In another report, Law et al. used a panel of cobalt tris (bipyridine) systems having an anticancer effect with collateral sensitivity toward multidrug resistance (MDR) cancers. The authors synthesized cobalt complexes (1–6) by a simple hydrothermal method from cobaltous chloride and ammonium hexafluorophosphate as precursors. (65) To confirm the anticancer abilities of the cobalt complexes in MDR cells, the authors utilized a panel of different MDR cells with different origins. The results showed that the cobalt complexes were able to specifically induce collateral sensitivity in Taxol-resistant and p53-deficient cancer cells.
A very interesting report has also been published by Jiang et al. using sodium chloride nanoparticles (SCNPs) synthesized from sodium oleate, molybdenum chloride, and oleylamine as a surfactant. (66) Mammalian cells maintain low ratios of intracellular to extracellular sodium and chloride and high ratios of potassium and these asymmetric ionic gradients are involved in the regulation and control of cell function. (67) Reducing and increasing extracellular sodium and chloride concentrations can cause cytoskeleton destruction, cell cycle arrest, and cell lysis. In light of all this information, the authors hypothesized that NaCl nanoparticles could be used as a Trojan horse strategy to deliver ions to cells and cause a disruption of ion homeostasis. (68) The NaCl nanoparticles enter the cell through endocytosis, bypassing the physiological ion-transport system, and release Na+ and Cl– ions inside cancer cells because of their high solubility, causing a surge of osmolarity and rapid cell lysis. (66)
All of these reports could support the efforts of scientists to develop self-therapeutic nanomaterials with future applications in cancer therapy.

4. Challenges and Future Perspectives

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There is an urgent need for researchers to develop self-therapeutic nanomaterials and successfully transition them from the bench to clinics. Since these are single-step therapeutic systems, there is no need to load any extra therapeutic compounds, such as the therapeutic systems in which nanomaterials are used only as drug carriers.
Although self-therapeutic nanomaterials still contain many drawbacks of the classical nanomaterials utilized for drug-delivery systems such as bioincompatibility and poor tumor-targeting ability, (69,70) their reduced complexity could assist in faster translation to the clinic. Combining the intrinsic therapeutic features of nanomaterials (71) without any external stimuli or other agents in one nanosystem could exhibit superior anticancer efficacy and reduce side effects, providing new strategies to fight cancer.
We also need to take into account that nanomaterials could possess quantum mechanical effects. According to the theory of quantum biology, cancer driver DNA mutations develop from the tunneling of protons that change the configuration of hydrogen bonding and allow hydrogen atoms to interact abnormally with DNA molecules. (72) Self-therapeutic nanomaterials could release the energy quanta (due to their wave-particle dual nature) or produce larger vibrations that cause changes in their frequencies at tumor sites and kill cancer cells. These larger vibrations or higher frequencies in the energy states of nanoparticles can produce heat in peritumoral regions or directly inside cancer cells and be effective in tumor metastasis treatment.
Together with the catalytic and deoxygenating effects described in this review, which could create unfavorable conditions such as hypoxia, high redox stress and inflammation, self-therapeutic nanomaterials could be a leading system in clinics in the near future if all of the associated problems could be minimized and act as “all in one” “magic bullet” that specifically targets the tumor and destroys it completely in a safe manner without any pain or other side effects. However, it remains to be seen if self-therapeutic nanomaterials are more potent than other therapeutic systems and able to inhibit cancer cells; otherwise it will be hard to breakdown the clinical barriers.

5. Conclusions

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In this review, we summarized the main available reports of self-therapeutic nanomaterials, focusing on the mechanism of action of the nanomaterials in regard to the inhibition of tumor cells. Inorganic nanomaterials that are used to kill cancer cells due to specific cancer inhibition mechanisms such as enzyme inhibition, oxygen capture approaches from tumor sites, and the production of free radicals in the tumor microenvironment were described. It was also highlighted that the self-therapeutic properties of organic nanomaterials such as self-assembled peptide-based nanomaterials and P-gp (MDR1 protein) inhibitors are useful for providing new opportunities to overcome MDR in the current therapeutic systems. Although there are several challenges related to this technology, its multiple interesting properties suggest that these therapeutic systems are very promising in regard to cancer therapy in the near future.

Author Information

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  • Corresponding Authors
    • Muhammad Adeel - PhD School in Science and Technology of Bio and Nanomaterials, Ca’ Foscari University of Venice, Venice 30170, Italy;  Department of Molecular Sciences and Nanosystems, Ca’ Foscari University of Venice, Venice 30170, Italy;  Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano 33081, Italy;  Orcidhttp://orcid.org/0000-0003-0916-4151;  Email: [email protected]
    • Flavio Rizzolio - Department of Molecular Sciences and Nanosystems, Ca’ Foscari University of Venice, Venice 30170, Italy;  Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano 33081, Italy;  Orcidhttp://orcid.org/0000-0002-3400-4363;  Email: [email protected]
  • Authors
    • Fahriye Duzagac - Department of Molecular Sciences and Nanosystems, Ca’ Foscari University of Venice, Venice 30170, Italy;  Orcidhttp://orcid.org/0000-0002-4130-2246
    • Vincenzo Canzonieri - Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano 33081, Italy;  Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste 34127, Italy;  Orcidhttp://orcid.org/0000-0001-6010-0976
  • Funding

    This work was financially supported by Fondazione AIRC per la Ricercasul Cancro (Grant AIRC IG23566) and Ministero della Salute–Ricerca Corrente (RC2020-Line 4).

  • Notes
    The authors declare no competing financial interest.

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    Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy
    Kane Robert C; Bross Peter F; Farrell Ann T; Pazdur Richard
    The oncologist (2003), 8 (6), 508-13 ISSN:1083-7159.
    Bortezomib (formerly PS-341), a promising new drug for the treatment of multiple myeloma, recently received accelerated approval from the U.S. Food and Drug Administration (FDA) for the therapy of patients with progressive myeloma after previous treatment. Two phase II studies of bortezomib used the same schedule of twice-weekly i.v. dosing for the first 2 weeks of each 3-week cycle. In a randomized study of 54 patients, two doses were compared (1.0 and 1.3 mg/m2) and objective responses occurred at both dose levels (23% versus 35%), including one complete response in each arm. In the other phase II study, 202 heavily pretreated patients (median of six prior therapies) all received the same schedule at 1.3 mg/m2. Of 188 evaluable patients, complete responses occurred in five (3%) and partial responses occurred in 47 (25%). The median duration of response was 365 days. The most clinically relevant adverse events were asthenic conditions, nausea, vomiting, diarrhea, thrombocytopenia, and a peripheral neuropathy that often was painful. This report highlights the FDA analysis supporting the accelerated approval.
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  17. 17
    Buac, D.; Shen, M.; Schmitt, S.; Rani Kona, F.; Deshmukh, R.; Zhang, Z.; Neslund-Dudas, C.; Mitra, B.; Dou, Q. P. From Bortezomib to Other Inhibitors of the Proteasome and Beyond. Curr. Pharm. Des. 2013, 19 (22), 4025– 4038,  DOI: 10.2174/1381612811319220012
    [Crossref], [PubMed], [CAS], Google Scholar
    17
    From bortezomib to other inhibitors of the proteasome and beyond
    Buac, Daniela; Shen, Min; Schmitt, Sara; Kona, Fathima Rani; Deshmukh, Rahul; Zhang, Zhen; Neslund-Dudas, Christine; Mitra, Bharati; Dou, Q. Ping
    Current Pharmaceutical Design (2013), 19 (22), 4025-4038CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)
    A review. The cancer drug discovery field has placed much emphasis on the identification of novel and cancer-specific mol. targets. A rich source of such targets for the design of novel anti-tumor agents is the ubiqutin-proteasome system (UP-S), a tightly regulated, highly specific pathway responsible for the vast majority of protein turnover within the cell. Because of its crit. role in almost all cell processes that ensure normal cellular function, its inhibition at one point in time was deemed non-specific and therefore not worth further investigation as a mol. drug target. However, today the proteasome is one of the most promising anti-cancer drug targets of the century. The discovery that tumor cells are in fact more sensitive to proteasome inhibitors than normal cells indeed paved the way for the design of its inhibitors. Such efforts have led to bortezomib, the first FDA approved proteasome inhibitor now used as a frontline treatment for newly diagnosed multiple myeloma (MM), relapsed/refractory MM and mantle cell lymphoma. Though successful in improving clin. outcomes for patients with hematol. malignancies, relapse often occurs in those who initially responded to bortezomib. Therefore, the acquisition of bortezomib resistance is a major issue with its therapy. Furthermore, some neuro-toxicities have been assocd. with bortezomib treatment and its efficacy in solid tumors is lacking. These observations have encouraged researchers to pursue the next generation of proteasome inhibitors, which would ideally overcome bortezomib resistance, have reduced toxicities and a broader range of anti-cancer activity. This review summarizes the success and limitations of bortezomib, and describes recent advances in the field, including, and most notably, the most recent FDA approval of carfilzomib in July, 2012, a second generation proteasome inhibitor. Other proteasome inhibitors currently in clin. trials and those that are currently exptl. grade will also be discussed.
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  18. 18
    Chen, D.; Frezza, M.; Schmitt, S.; Kanwar, J.; P. Dou, Q. Bortezomib as the First Proteasome Inhibitor Anticancer Drug: Current Status and Future Perspectives. Curr. Cancer Drug Targets 2011, 11 (3), 239– 253,  DOI: 10.2174/156800911794519752
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    18
    Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives
    Chen, D.; Frezza, M.; Schmitt, S.; Kanwar, J.; Dou, Q. P.
    Current Cancer Drug Targets (2011), 11 (3), 239-253CODEN: CCDTB9; ISSN:1568-0096. (Bentham Science Publishers Ltd.)
    A review. Targeting the ubiquitin-proteasome pathway has emerged as a rational approach in the treatment of human cancer. Based on pos. preclin. and clin. studies, bortezomib was subsequently approved for the clin. use as a front-line treatment for newly diagnosed multiple myeloma patients and for the treatment of relapsed/refractory multiple myeloma and mantle cell lymphoma, for which this drug has become the staple of treatment. The approval of bortezomib by the US Food and Drug Administration (FDA) represented a significant milestone as the first proteasome inhibitor to be implemented in the treatment of malignant disease. Bortezomib has shown a pos. clin. benefit either alone or as a part of combination therapy to induce chemo-/radio-sensitization or overcome drug resistance. One of the major mechanisms of bortezomib assocd. with its anticancer activity is through upregulation of NOXA, which is a proapoptotic protein, and NOXA may interact with the anti-apoptotic proteins of Bcl-2 subfamily Bcl-XL and Bcl-2, and result in apoptotic cell death in malignant cells. Another important mechanism of bortezomib is through suppression of the NF-κB signaling pathway resulting in the down-regulation of its anti-apoptotic target genes. Although the majority of success achieved with bortezomib has been in hematol. malignancies, its effect toward solid tumors has been less than encouraging. Addnl., the widespread clin. use of bortezomib continues to be hampered by the appearance of dose-limiting toxicities, drug-resistance and interference by some natural compds. These findings could help guide physicians in refining the clin. use of bortezomib, and encourage basic scientists to generate next generation proteasome inhibitors that broaden the spectrum of efficacy and produce a more durable clin. response in cancer patients. Other desirable applications for the use of proteasome inhibitors include the development of inhibitors against specific E3 ligases, which act at an early step in the ubiquitin-proteasome pathway, and the discovery of less toxic and novel proteasome inhibitors from natural products and traditional medicines, which may provide more viable drug candidates for cancer chemoprevention and the treatment of cancer patients in the future.
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  19. 19
    Pizzorno, L. Nothing Boring about Boron. Integr. Med. 2015, 14 (4), 35– 48
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    19
    Nothing Boring About Boron
    Pizzorno Lara
    Integrative medicine (Encinitas, Calif.) (2015), 14 (4), 35-48 ISSN:1546-993X.
    The trace mineral boron is a micronutrient with diverse and vitally important roles in metabolism that render it necessary for plant, animal, and human health, and as recent research suggests, possibly for the evolution of life on Earth. As the current article shows, boron has been proven to be an important trace mineral because it (1) is essential for the growth and maintenance of bone; (2) greatly improves wound healing; (3) beneficially impacts the body's use of estrogen, testosterone, and vitamin D; (4) boosts magnesium absorption; (5) reduces levels of inflammatory biomarkers, such as high-sensitivity C-reactive protein (hs-CRP) and tumor necrosis factor α (TNF-α); (6) raises levels of antioxidant enzymes, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase; (7) protects against pesticide-induced oxidative stress and heavy-metal toxicity; (8) improves the brains electrical activity, cognitive performance, and short-term memory for elders; (9) influences the formation and activity of key biomolecules, such as S-adenosyl methionine (SAM-e) and nicotinamide adenine dinucleotide (NAD(+)); (10) has demonstrated preventive and therapeutic effects in a number of cancers, such as prostate, cervical, and lung cancers, and multiple and non-Hodgkin's lymphoma; and (11) may help ameliorate the adverse effects of traditional chemotherapeutic agents. In none of the numerous studies conducted to date, however, do boron's beneficial effects appear at intakes > 3 mg/d. No estimated average requirements (EARs) or dietary reference intakes (DRIs) have been set for boron-only an upper intake level (UL) of 20 mg/d for individuals aged ≥ 18 y. The absence of studies showing harm in conjunction with the substantial number of articles showing benefits support the consideration of boron supplementation of 3 mg/d for any individual who is consuming a diet lacking in fruits and vegetables or who is at risk for or has osteopenia; osteoporosis; osteoarthritis (OA); or breast, prostate, or lung cancer.
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  20. 20
    Barranco, W. T.; Hudak, P. F.; Eckhert, C. D. Evaluation of Ecological and in Vitro Effects of Boron on Prostate Cancer Risk (United States). Cancer Causes Control 2007, 18, 71– 77,  DOI: 10.1007/s10552-006-0077-8
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    20
    Evaluation of ecological and in vitro effects of boron on prostate cancer risk (United States)
    Barranco Wade T; Hudak Paul F; Eckhert Curtis D
    Cancer causes & control : CCC (2007), 18 (1), 71-7 ISSN:0957-5243.
    OBJECTIVE: To determine: (1) the correlation of prostate cancer incidence and mortality with groundwater boron and selenium concentrations; and (2) the impact of boron on prostate cancer cell proliferation during co-treatment with alternative chemo-preventative agents, along with boron pre-treatment effects on cell sensitivity to ionizing radiation. METHODS: For regression analysis, data on prostate cancer incidence and mortality were obtained from the Texas Cancer Registry, while groundwater boron and selenium concentrations were derived from the Texas Water Development Board. Cultured DU-145 prostate cancer cells were used to assess the impact of boric acid on cell proliferation when applied in combination with selenomethionine and genistein, or preceding radiation exposure. RESULTS: Groundwater boron levels correlated with a decrease in prostate cancer incidence (R = 0.6) and mortality (R = 0.6) in state planning regions, whereas selenium did not (R = 0.1; R = 0.2). Growth inhibition was greater during combined treatments of boric acid and selenomethionine, or boric acid and genistein, versus singular treatments. 8-day boric acid pre-exposure enhanced the toxicity of ionizing radiation treatment, while dose-dependently decreasing the expression of anti-apoptotic protein Bcl-2. CONCLUSIONS: Increased groundwater boron concentrations, across the state of Texas, correlate with reduced risk of prostate cancer incidence and mortality. Also, boric acid improves the anti-proliferative effectiveness of chemo-preventative agents, selenomethionine and genistein, while enhancing ionizing radiation cell kill.
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  21. 21
    I. Scorei, R.; Popa, R. Boron-Containing Compounds as Preventive and Chemotherapeutic Agents for Cancer. Anti-Cancer Agents Med. Chem. 2010, 10 (4), 346– 351,  DOI: 10.2174/187152010791162289
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    There is no corresponding record for this reference.
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    Baker, S. J.; Ding, C. Z.; Akama, T.; Zhang, Y. K.; Hernandez, V.; Xia, Y. Therapeutic Potential of Boron-Containing Compounds. Future Med. Chem. 2009, 1 (7), 1275– 1288,  DOI: 10.4155/fmc.09.71
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    Therapeutic potential of boron-containing compounds
    Baker, Stephen J.; Ding, Charles Z.; Akama, Tsutomu; Zhang, Yong-Kang; Hernandez, Vincent; Xia, Yi
    Future Medicinal Chemistry (2009), 1 (7), 1275-1288CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)
    A review. Relative to C, H, N, and O2, very little is currently known about B in therapeutics. In addn., there are very few boron-contg. natural products identified to date to serve as leads for medicinal chemists. Perceived risks of using B and lack of synthetic methods to handle boron-contg. compds. have caused the medicinal chem. community to shy away from using the atom. However, phys., chem. and biol. properties of B offer medicinal chemists a rare opportunity to explore and pioneer new areas of drug discovery. B therapeutics are emerging that show different modes of inhibition against a variety of biol. targets. With one B-contg. therapeutic agent on the market and several more in various stages of clin. trials, the occurrence of this class of compd. is likely to grow over the next decade and B could become widely accepted as a useful element in future drug discovery.
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  23. 23
    Li, X.; Wang, X.; Zhang, J.; Hanagata, N.; Wang, X.; Weng, Q.; Ito, A.; Bando, Y.; Golberg, D. Hollow Boron Nitride Nanospheres as Boron Reservoir for Prostate Cancer Treatment. Nat. Commun. 2017, 8, 13936,  DOI: 10.1038/ncomms13936
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    23
    Hollow boron nitride nanospheres as boron reservoir for prostate cancer treatment
    Li, Xia; Wang, Xiupeng; Zhang, Jun; Hanagata, Nobutaka; Wang, Xuebin; Weng, Qunhong; Ito, Atsuo; Bando, Yoshio; Golberg, Dmitri
    Nature Communications (2017), 8 (), 13936CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)
    High global incidence of prostate cancer has led to a focus on prevention and treatment strategies to reduce the impact of this disease in public health. Boron compds. are increasingly recognized as preventative and chemotherapeutic agents. However, systemic administration of sol. boron compds. is hampered by their short half-life and low effectiveness. Here we report on hollow boron nitride (BN) spheres with controlled crystallinity and boron release that decrease cell viability and increase prostate cancer cell apoptosis. In vivo expts. on s.c. tumor mouse models treated with BN spheres demonstrated significant suppression of tumor growth. An orthotopic tumor growth model was also utilized and further confirmed the in vivo anti-cancer efficacy of BN spheres. Moreover, the administration of hollow BN spheres with paclitaxel leads to synergetic effects in the suppression of tumor growth. The work demonstrates that hollow BN spheres may function as a new agent for prostate cancer treatment.
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    Emanet Ciofani, M.; Şen, Ö.; Culha, M. Hexagonal Boron Nitride Nanoparticles for Prostate Cancer Treatment. ACS Appl. Nano Mater. 2020, 3 (3), 2364– 2372,  DOI: 10.1021/acsanm.9b02486
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    24
    Hexagonal Boron Nitride Nanoparticles for Prostate Cancer Treatment
    Emanet Ciofani, Melis; Sen, Ozlem; Culha, Mustafa
    ACS Applied Nano Materials (2020), 3 (3), 2364-2372CODEN: AANMF6; ISSN:2574-0970. (American Chemical Society)
    In recent years, hexagonal boron nitride (hBN) nanoparticles have gained significant interest in the medical and biomedical fields owing to their unique physicochem. properties including high surface area, low toxicity, and slow degrdn. in aq. media. With its possible degrdn. product boric acid (BA), a compd. of an essential element for the healthy function of biomachinery, a comparative evaluation of hBN and BA can reveal important information about the possible use of these novel materials in medicine. In this study, the influence of hBN and BA on prostate cancer cells was comparatively investigated by emphasizing the effect mechanisms through a no. of mol. tests. First, the high cellular internalization capacity of hBN, as well as the high cellular sensitivity of prostate cancer cells that cause a significant cell viability decrease on the contrary of healthy cells, was evaluated. In order to evaluate their cancer repression effect, mitochondrial dysfunction, reactive oxygen species (ROS) prodn., and cell death mechanisms were investigated. Finally, the metastatic capacities of the cancer cells were tested by monitoring the cytoskeleton structures and migration capacity of cells exposed to hBN. The results clearly indicate that hBN promotes prostate cancer cell apoptosis by seriously increasing ROS prodn. Moreover, their metastatic capacity decrement encouraged us to exploit hBN as a safe therapeutic agent against prostate cancer.
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  25. 25
    Gallardo-Williams, M. T.; Chapin, R. E.; King, P. E.; Moser, G. J.; Goldsworthy, T. L.; Morrison, J. P.; Maronpot, R. R. Boron Supplementation Inhibits the Growth and Local Expression of IGF-1 in Human Prostate Adenocarcinoma (LNCaP) Tumors in Nude Mice. Toxicol. Pathol. 2004, 32 (1), 73– 78,  DOI: 10.1080/01926230490260899
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    25
    Boron Supplementation Inhibits the Growth and Local Expression of IGF-1 in Human Prostate Adenocarcinoma (LNCaP) Tumors in Nude Mice
    Gallardo-Williams, Maria T.; Chapin, Robert E.; King, Paula E.; Moser, Glenda J.; Goldsworthy, Thomas L.; Morrison, James P.; Maronpot, Robert R.
    Toxicologic Pathology (2004), 32 (1), 73-78CODEN: TOPADD; ISSN:0192-6233. (Taylor & Francis, Inc.)
    Prostate-specific antigen (PSA) is a serine protease and one of the most abundant proteins secreted by the human prostate epithelium. PSA is used as a well-established marker of prostate cancer. The involvement of PSA in several early events leading to the development of malignant prostate tumors has made it a target for prevention and intervention. It is thought that PSA cleaves insulin-like growth factor binding protein-3 (IGFBP-3), providing increased local levels of IGF-1, leading to tumor growth. Sep., there are data that suggest an enzymic regulatory role for dietary boron, which is a serine protease inhibitor. In this study we have addressed the use of boric acid as a PSA inhibitor in an animal study. We have previously reported that low concns. (6 ug/mL) of boric acid can partially inhibit the proteolytic activity of purified PSA towards a synthetic fluorogenic substrate. Also, by Western blot we have followed the degrdn. of fibronectin by enzymically active PSA and have found significant inhibition in the presence of boric acid. We proposed that dietary supplementation with boric acid would inhibit PSA and reduce the development and proliferation of prostate carcinomas in an animal model. We tested this hypothesis using nude mice implanted s.c. with LNCaP cells in Matrigel. Two groups (10 animals/group) were dosed with boric acid solns. (1.7, 9.0 mgB/kg/day) by gavage. Control group received only water. Tumor sizes were measured weekly for 8 wk. Serum PSA and IGF-1 levels were detd. at terminal sacrifice. The size of tumors was decreased in mice exposed to the low and high dose of boric acid by 38% and 25%, resp. Serum PSA levels decreased by 88.6% and 86.4%, resp., as compared to the control group. There were morphol. differences between the tumors in control and boron-dosed animals, including a significantly lower incidence of mitotic figures in the boron-supplemented groups. Circulating IGF-1 levels were not different among groups, though expression of IGF-1 in the tumors was markedly reduced by boron treatment, which we have shown by immunohistochem. These data indicate that low-level dietary boron supplementation reduced tumor size and content of a tumor trophic factor, IGF-1. This promising model is being evaluated in further studies.
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    Cohen, P.; Peehl, D. M.; Graves, H. C. B.; Rosenfeld, R. G. Biological Effects of Prostate Specific Antigen as an Insulin-like Growth Factor Binding Protein-3 Protease. J. Endocrinol. 1994, 142 (3), 407– 415,  DOI: 10.1677/joe.0.1420407
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    26
    Biological effects of prostate specific antigen as an insulin-like growth factor binding protein-3 protease
    Cohen, P.; Peehl, D. M.; Graves, H. C. B.; Rosenfield, R. G.
    Journal of Endocrinology (1994), 142 (3), 407-15CODEN: JOENAK; ISSN:0022-0795.
    Prostate specific antigen (PSA) is an insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) protease found in seminal plasma and produced by prostatic epithelial cells (PC-E) in vivo. The authors examd. the effects of PSA-proteolysis of IGFBP-3 on the affinity of IGFBP-3 fragments for IGFs and on the mitogenic action of IGFs on PCE-E. Recombinant human IGFBP-3 was cleaved by PSA, then incubated with 125I-IGF-I or -II in the presence of varying concns. of unlabeled peptides, and then crosslinking electrophoresis and densitometric anal. were performed. While the affinity of IGF-II for the PSA-generated IGFBP-3 fragments fell slightly compared to intact IGFBP-3, the affinity of the PSA-generated IGFBP-3 fragments for IGF-I fell by ten fold. The addn. of IGF-I or -II to PC-E in serum-free culture conditions resulted in a two-fold stimulation of cell no. compared to control. The presence of IGFBP-3 in the media blocked the IGF-induced stimulation, but had no independent effect in the absence of IGFs. When PSA was added to PC-E cultures to which both IGF-I or -II and IGFBP-3 were added, the inhibitory effects of IGFBP-3 on IGF mitogenesis were reversed. Apparently, PSA decreases the affinity of IGFBP-3 for IGF and can potentiate IGF action in the presence of inhibitory IGFBP-3. This phenomenon may contribute to normal and malignant prostate growth.
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    Tian, Y.; Guo, Z.; Zhang, T.; Lin, H.; Li, Z.; Chen, J.; Deng, S.; Liu, F. Inorganic Boron-Based Nanostructures: Synthesis, Optoelectronic Properties, and Prospective Applications. Nanomaterials 2019, 9 (4), 538,  DOI: 10.3390/nano9040538
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    27
    Inorganic boron-based nanostructures: synthesis, optoelectronic properties, and prospective applications
    Tian, Yan; Guo, Zekun; Zhang, Tong; Lin, Haojian; Li, Zijuan; Chen, Jun; Deng, Shaozhi; Liu, Fei
    Nanomaterials (2019), 9 (4), 538CODEN: NANOKO; ISSN:2079-4991. (MDPI AG)
    A review. Inorg. boron-based nanostructures have great potential for field emission (FE), flexible displays, superconductors, and energy storage because of their high m.p., low d., extreme hardness, and good chem. stability. Until now, most researchers have been focused on one-dimensional (1D) boron-based nanostructures (rare earth boride (REB6) nanowires, boron nanowires, and nanotubes). Currently, two-dimensional (2D) borophene attracts most of the attention, due to its unique phys. and chem. properties, which make it quite different from its corresponding bulk counterpart. Here, we offer a comprehensive review on the synthesis methods and optoelectronics properties of inorg. boron-based nanostructures, which are mainly concd. on 1D rare earth boride nanowires, boron monoelement nanowires, and nanotubes, as well as 2D borophene and borophane. In Section I, the synthesis methods of inorg. boron-based nanostructures are systematically introduced. In Section II, we classify their optical and elec. transport properties (field emission, optical absorption, and photoconductive properties). In the last section, we evaluate the optoelectronic behaviors of the known inorg. boron-based nanostructures and propose their future applications.
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    Mateti, S.; Wong, C. S.; Liu, Z.; Yang, W.; Li, Y.; Li, L. H.; Chen, Y. Biocompatibility of Boron Nitride Nanosheets. Nano Res. 2018, 11 (1), 334– 342,  DOI: 10.1007/s12274-017-1635-y
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    Biocompatibility of boron nitride nanosheets
    Mateti, Srikanth; Wong, Cynthia S.; Liu, Zhen; Yang, Wenrong; Li, Yuncang; Li, Lu Hua; Chen, Ying
    Nano Research (2018), 11 (1), 334-342CODEN: NRAEB5; ISSN:1998-0000. (Springer GmbH)
    The properties and applications of boron nitride (BN) nanosheets are complementary to those of graphene, with advantages in chem. and thermal stability. Biocompatibility is an important property for future biomedical applications but has not been investigated exptl. We studied the biocompatibility of BN nanosheets of different sizes and compared it with that of BN nanoparticles in osteoblast-like cells (SaOS2). Our results showed that the biocompatibility of BN nanomaterials depends on their size, shape, structure, and surface chem. properties. ESR measurement revealed that unsatd. B atoms located at the nanosheet edges or on the particle surface are responsible for the cell death.
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    Orme, M. E.; Chaplain, M. A. J. Two-Dimensional Models of Tumour Angiogenesis and Anti-Angiogenesis Strategies. IMA J. Math. Appl. Med. Biol. 1997, 14 (3), 189– 205,  DOI: 10.1093/imammb/14.3.189
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    29
    Two-dimensional models of tumour angiogenesis and anti-angiogenesis strategies
    Orme M E; Chaplain M A
    IMA journal of mathematics applied in medicine and biology (1997), 14 (3), 189-205 ISSN:0265-0746.
    There is a very strong link between the vascularization of a tumour and the spread of the disease, both locally and to distant sites (Gimbrone et al., 1974, J. Natl. Cancer Inst. 52, 413-27; Muthukkaruppan et al., 1982, J. Natl. Cancer Inst. 69, 699-704; Ellis & Fiddler, 1995, Lancet 346, 388-9). A tumour becomes vascularized by a process known as angiogenesis. Tumour angiogenesis is initiated by the release of diffusible substances by the tumour, whereby neighbouring capillary vessels are stimulated to grow and eventually penetrate the tumour. Anti-angiogenesis has been proposed as a potential strategy for the treatment of cancer (Folkman, 1995, Nature Med. 1, 21-31; Harris et al., 1996, Breast Cancer Res. Treat. 38, 97-108). In this paper, a mathematical model of the development of the tumour vasculature is presented. By suitable manipulation of the model parameters, we simulate various anti-angiogenesis strategies and we examine the roles that haptotaxis and chemotaxis may play during the growth of the neovasculature. The model is simulated in two space dimensions (on a square domain) so that it is, in theory, experimentally reproducible and any predictions of the model can therefore be tested.
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    Hillen, F.; Griffioen, A. W. Tumour Vascularization: Sprouting Angiogenesis and Beyond. Cancer Metastasis Rev. 2007, 26 (3–4), 489– 502,  DOI: 10.1007/s10555-007-9094-7
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    30
    Tumour vascularization: sprouting angiogenesis and beyond
    Hillen Femke; Griffioen Arjan W
    Cancer metastasis reviews (2007), 26 (3-4), 489-502 ISSN:0167-7659.
    Tumour angiogenesis is a fast growing domain in tumour biology. Many growth factors and mechanisms have been unravelled. For almost 30 years, the sprouting of new vessels out of existing ones was considered as an exclusive way of tumour vascularisation. However, over the last years several additional mechanisms have been identified. With the discovery of the contribution of intussusceptive angiogenesis, recruitment of endothelial progenitor cells, vessel co-option, vasculogenic mimicry and lymphangiogenesis to tumour growth, anti-tumour targeting strategies will be more complex than initially thought. This review highlights these processes and intervention as a potential application in cancer therapy. It is concluded that future anti-vascular therapies might be most beneficial when based on multimodal anti-angiogenic, anti-vasculogenic mimicry and anti-lymphangiogenic strategies.
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    Nishida, N.; Yano, H.; Nishida, T.; Kamura, T.; Kojiro, M. Angiogenesis in Cancer. Vasc. Health Risk Manag. 2006, 2 (3), 213– 219,  DOI: 10.2147/vhrm.2006.2.3.213
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    Angiogenesis in cancer
    Nishida, Naoyo; Yano, Hirohisa; Nishida, Takashi; Kamura, Toshiharu; Kojiro, Masamichi
    Vascular Health and Risk Management (2006), 2 (3), 213-219CODEN: VHRMAT; ISSN:1176-6344. (Dove Medical Press (NZ) Ltd.)
    A review. New growth in the vascular network is important since the proliferation, as well as metastatic spread, of cancer cells depends on an adequate supply of oxygen and nutrients and the removal of waste products. New blood and lymphatic vessels form through processes called angiogenesis and lymphangiogenesis, resp. Angiogenesis is regulated by both activator and inhibitor mols. More than a dozen different proteins have been identified as angiogenic activators and inhibitors. Levels of expression of angiogenic factors reflect the aggressiveness of tumor cells. The discovery of angiogenic inhibitors should help to reduce both morbidity and mortality from carcinomas. Thousands of patients have received antiangiogenic therapy to date. Despite their theor. efficacy, antiangiogenic treatments have not proved beneficial in terms of long-term survival. There is an urgent need for a new comprehensive treatment strategy combining antiangiogenic agents with conventional cytoreductive treatments in the control of cancer.
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  32. 32
    Abunahla, H.; Mohammad, B.; Alazzam, A.; Jaoude, M. A.; Al-Qutayri, M.; Abdul Hadi, S.; Al-Sarawi, S. F. MOMSense: Metal-Oxide-Metal Elementary Glucose Sensor. Sci. Rep. 2019, 9 (1), 5524,  DOI: 10.1038/s41598-019-41892-w
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    MOMSense: Metal-Oxide-Metal Elementary Glucose Sensor
    Abunahla Heba; Mohammad Baker; Al-Qutayri Mahmoud; Abdul Hadi Sabina; Alazzam Anas; Jaoude Maguy Abi; Al-Sarawi Said F
    Scientific reports (2019), 9 (1), 5524 ISSN:.
    In this paper, we present a novel Pt/CuO/Pt metal-oxide-metal (MOM) glucose sensor. The devices are fabricated using a simple, low-cost standard photolithography process. The unique planar structure of the device provides a large electrochemically active surface area, which acts as a nonenzymatic reservoir for glucose oxidation. The sensor has a linear sensing range between 2.2 mM and 10 mM of glucose concentration, which covers the blood glucose levels for an adult human. The distinguishing property of this sensor is its ability to measure glucose at neutral pH conditions (i.e. pH = 7). Furthermore, the dilution step commonly needed for CuO-based nonenzymatic electrochemical sensors to achieve an alkaline medium, which is essential to perform redox reactions in the absence of glucose oxidase, is eliminated, resulting in a lower-cost and more compact device.
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    Kerbel, R. S.; Kamen, B. A. The Anti-Angiogenic Basis of Metronomic Chemotherapy. Nat. Rev. Cancer 2004, 4 (6), 423– 436,  DOI: 10.1038/nrc1369
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    The anti-angiogenic basis of metronomic chemotherapy
    Kerbel, Robert S.; Kamen, Barton A.
    Nature Reviews Cancer (2004), 4 (6), 423-436CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)
    A review. In addn. to proliferating cancer cells and various types of normal cells, such as those of the bone marrow, conventional cytotoxic chemotherapeutics affect the endothelium of the growing tumor vasculature. The anti-angiogenic efficacy of chemotherapy seems to be optimized by administering comparatively low doses of drug on a frequent or continuous schedule, with no extended interruptions - sometimes referred to as 'metronomic' chemotherapy. In addn. to reduced acute toxicity, the efficacy of metronomic chemotherapy seems to increase when administered in combination with specific anti-angiogenic drugs. Gaining better insight into the mechanisms of these effects could lessen or even eliminate the empiricism used to det. the optimal dose and schedule for metronomic chemotherapy regimens.
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    Yoncheva, K.; Momekov, G. Antiangiogenic Anticancer Strategy Based on Nanoparticulate Systems. Expert Opin. Drug Delivery 2011, 8 (8), 1041– 1056,  DOI: 10.1517/17425247.2011.585155
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    Antiangiogenic anticancer strategy based on nanoparticulate systems
    Yoncheva, Krassimira; Momekov, Georgi
    Expert Opinion on Drug Delivery (2011), 8 (8), 1041-1056CODEN: EODDAW; ISSN:1742-5247. (Informa Healthcare)
    A review. Introduction: Angiogenesis is a process that provides a blood supply for cancer cells. The discovery that the blockade of this blood supply results in the inhibition of cancer cell growth has been applied in cancer treatment. This antiangiogenic strategy is mainly directed at the inhibition of the binding process between proangiogenic growth factors and their receptors or the inhibition of the activity of proteolytic enzymes of the extracellular matrix. The toxicity of some antiangiogenic agents, such as small-mol. inhibitors, and the instability of antiangiogenic proteins require their formulation in an appropriate delivery system. On the other hand, active drug targeting to selective markers expressed on tumor vasculature could improve antiangiogenic treatment.Areas covered: The present review focuses on nanoparticulate systems (nanoparticles, liposomes, polymeric micelles, etc.) because their properties could enable both the targeting of endothelial cells and the efficient delivery of antiangiogenic agents. The most important properties of nanoparticles that influence both processes, such as their size, charge and surface modification, are also discussed. Various examples illustrating the targeting ability of nanoparticles are reported, in particular conjugated nanoparticles targeting VEGF and its receptors, fibroblast growth factor and its receptors, EGFRs, MMPs, tubulin function and so on.Expert opinion: Targeting of nanoparticles (e.g., by tumor-penetrating peptides) allows the co-administration of antiangiogenic and anticancer drugs, facilitates drug penetration into extravascular tumor tissue and improves the therapeutic effect at reduced drug doses.
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    Ma, J.; Pulfer, S.; Li, S.; Chu, J.; Reed, K.; Gallo, J. M. Pharmacodynamic-Mediated Reduction of Temozolomide Tumor Concentrations by the Angiogenesis Inhibitor TNP-470. Cancer Res. 2001, 61 (14), 5491– 5498
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    Pharmacodynamic-mediated reduction of temozolomide tumor concentrations by the angiogenesis inhibitor TNP-470
    Ma, Jianguo; Pulfer, Sharon; Li, Shaolan; Chu, Jianxiong; Reed, Karin; Gallo, James M.
    Cancer Research (2001), 61 (14), 5491-5498CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)
    This work evaluated a potential drug interaction between the angiogenesis inhibitor O-(N-chloroacetylcarbamoyl)furnagillol (TNP-470) and the alkylating agent temozolomide (TMZ) in xenograft models that differentially expressed vascular endothelial growth factor (VEGF), a driving force for angiogenesis. Nude rats bearing either s.c. low-VEGF (V-) or high-VEGF (V+) or intracerebral V+ gliomas were administered either a multiple-dose regimen of TNP-470 or vehicle control. One day after the last dose of vehicle or TNP-470, a steady-state dosage regimen of TMZ was administered with subsequent collection and HPLC anal. of plasma and either tumor homogenate or tumor microdialysis steady-state TMZ concns., and in some cases [5-(3-methyltriazen-1-yl)imidazole-4-carboximide] MTIC, its active metabolite. Microvessel d. (MVD) was quantitated by image anal. with an anti-CD31 method. Statistical analyses of pharmacokinetic and pharmacodynamic end points in the control and TNP-470-treated groups were completed by nonparametric tests. In both the s.c. and intracerebral V+ models, TNP-470 treatment reduced tumor TMZ concns. and tumor:plasma concn. ratios compared with controls, being reduced an av. of 25% and 50% in the s.c. and intracerebral tumors, resp. MTIC concns. in V+ s.c. tumors also were reduced by 50% in the presence of TNP-470. Consistent with the lower extent of neovascularization in the V- tumors, tumor TMZ and MTIC concns. were not different in s.c. tumors between the TNP-470-treated and control groups. MVD was reduced by TNP-470 compared with controls in the V+ tumors, but was unaltered in V- tumors, attesting to the use of MVD as a pharmacodynamic end point and the effectiveness of TNP-470 as an angiogenesis inhibitor. Angiogenesis inhibitors' pharmacodynamic actions on tumor angiogenesis can reduce tumor concns. of coadministered anticancer agents.
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    Desai, N. Challenges in Development of Nanoparticle-Based Therapeutics. AAPS J. 2012, 14 (2), 282– 295,  DOI: 10.1208/s12248-012-9339-4
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    Challenges in Development of Nanoparticle-Based Therapeutics
    Desai, Neil
    AAPS Journal (2012), 14 (2), 282-295CODEN: AJAOB6; ISSN:1550-7416. (Springer)
    A review. In recent years, nanotechnol. has been increasingly applied to the area of drug development. Nanoparticle-based therapeutics can confer the ability to overcome biol. barriers, effectively deliver hydrophobic drugs and biologics, and preferentially target sites of disease. However, despite these potential advantages, only a relatively small no. of nanoparticle-based medicines have been approved for clin. use, with numerous challenges and hurdles at different stages of development. The complexity of nanoparticles as multi-component three dimensional constructs requires careful design and engineering, detailed orthogonal anal. methods, and reproducible scale-up and manufg. process to achieve a consistent product with the intended physicochem. characteristics, biol. behaviors, and pharmacol. profiles. The safety and efficacy of nanomedicines can be influenced by minor variations in multiple parameters and need to be carefully examd. in preclin. and clin. studies, particularly in context of the biodistribution, targeting to intended sites, and potential immune toxicities. Overall, nanomedicines may present addnl. development and regulatory considerations compared with conventional medicines, and while there is generally a lack of regulatory stds. in the examn. of nanoparticle-based medicines as a unique category of therapeutic agents, efforts are being made in this direction. This review summarizes challenges likely to be encountered during the development and approval of nanoparticle-based therapeutics, and discusses potential strategies for drug developers and regulatory agencies to accelerate the growth of this important field.
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    Mukherjee, S.; Patra, C. R. Therapeutic Application of Anti-Angiogenic Nanomaterials in Cancers. Nanoscale 2016, 8 (25), 12444– 12470,  DOI: 10.1039/C5NR07887C
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    Therapeutic application of anti-angiogenic nanomaterials in cancers
    Mukherjee, Sudip; Patra, Chitta Ranjan
    Nanoscale (2016), 8 (25), 12444-12470CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
    Angiogenesis, the formation of new blood vessels from pre-existing vasculature, plays a vital role in physiol. and pathol. processes (embryonic development, wound healing, tumor growth and metastasis). The overall balance of angiogenesis inside the human body is maintained by pro- and anti-angiogenic signals. The processes by which drugs inhibit angiogenesis as well as tumor growth are called the anti-angiogenesis technique, a most promising cancer treatment strategy. Over the last couple of decades, scientists have been developing angiogenesis inhibitors for the treatment of cancers. However, conventional anti-angiogenic therapy has several limitations including drug resistance that can create problems for a successful therapeutic strategy. Therefore, a new comprehensive treatment strategy using antiangiogenic agents for the treatment of cancer is urgently needed. Recently researchers have been developing and designing several nanoparticles that show anti-angiogenic properties. These nanomedicines could be useful as an alternative strategy for the treatment of various cancers using anti-angiogenic therapy. In this review article, we critically focus on the potential application of anti-angiogenic nanomaterial and nanoparticle based drug/siRNA/peptide delivery systems in cancer therapeutics. We also discuss the basic and clin. perspectives of anti-angiogenesis therapy, highlighting its importance in tumor angiogenesis, current status and future prospects and challenges.
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    Zhang, C.; Ni, D.; Liu, Y.; Yao, H.; Bu, W.; Shi, J. Magnesium Silicide Nanoparticles as a Deoxygenation Agent for Cancer Starvation Therapy. Nat. Nanotechnol. 2017, 12 (4), 378– 386,  DOI: 10.1038/nnano.2016.280
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    Magnesium silicide nanoparticles as a deoxygenation agent for cancer starvation therapy
    Zhang, Chen; Ni, Dalong; Liu, Yanyan; Yao, Heliang; Bu, Wenbo; Shi, Jianlin
    Nature Nanotechnology (2017), 12 (4), 378-386CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)
    A material that rapidly absorbs mol. oxygen (known as an oxygen scavenger or deoxygenation agent (DOA)) has various industrial applications, such as in food preservation, anticorrosion of metal and coal deoxidn. Given that oxygen is vital to cancer growth, to starve tumors through the consumption of intratumoral oxygen is a potentially useful strategy in fighting cancer. Here we show that an injectable polymer-modified magnesium silicide (Mg2Si) nanoparticle can act as a DOA by scavenging oxygen in tumors and form byproducts that block tumor capillaries from being reoxygenated. The nanoparticles are prepd. by a self-propagating high-temp. synthesis strategy. In the acidic tumor microenvironment, the Mg2Si releases silane, which efficiently reacts with both tissue-dissolved and Hb-bound oxygen to form silicon oxide (SiO2) aggregates. This in situ formation of SiO2 blocks the tumor blood capillaries and prevents tumors from receiving new supplies of oxygen and nutrients.
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    Ranji-Burachaloo, H.; Karimi, F.; Xie, K.; Fu, Q.; Gurr, P. A.; Dunstan, D. E.; Qiao, G. G. MOF-Mediated Destruction of Cancer Using the Cell’s Own Hydrogen Peroxide. ACS Appl. Mater. Interfaces 2017, 9 (39), 33599– 33608,  DOI: 10.1021/acsami.7b07981
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    MOF-Mediated Destruction of Cancer Using the Cell's Own Hydrogen Peroxide
    Ranji-Burachaloo, Hadi; Karimi, Fatemeh; Xie, Ke; Fu, Qiang; Gurr, Paul A.; Dunstan, Dave E.; Qiao, Greg G.
    ACS Applied Materials & Interfaces (2017), 9 (39), 33599-33608CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
    A novel reduced iron metal-org. framework nanoparticle with cytotoxicity specific to cancer cells is presented. This nanoparticle was prepd. via a hydrothermal method, reduced using hydroquinone, and finally conjugated with folic acid (namely, rMOF-FA). The synthesized nanoparticle shows the controlled release of iron in an acidic ex-vivo environment. Iron present on the rMOF-FA and released into soln. can react with high levels of hydrogen peroxide found specifically in cancer cells to increase the hydroxyl radical concn. The hydroxyl radicals oxidize proteins, lipids, and/or DNA within the biol. system to decrease cell viability. In vitro expts. demonstrate that this novel nanoparticle is cytotoxic to cancer cells (HeLa) through generation of OH• inside the cells. At low concns. of rMOF-FA, the cancer cell viability decreases dramatically, with no obvious redn. of normal cell (NIH-3T3) viability. The calcd. half-max. inhibitory concn. value (IC50) was 43 μg/mL for HeLa cells, which was significantly higher than 105 μg/mL for NIH-3T3. This work thus demonstrates a new type of agent for controlled hydroxyl radical generation using the Fenton reaction to kill the tumor cells.
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    Qian, X.; Zhang, J.; Gu, Z.; Chen, Y. Nanocatalysts-Augmented Fenton Chemical Reaction for Nanocatalytic Tumor Therapy. Biomaterials 2019, 211, 1– 13,  DOI: 10.1016/j.biomaterials.2019.04.023
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    Nanocatalysts-augmented Fenton chemical reaction for nanocatalytic tumor therapy
    Qian, Xiaoqin; Zhang, Jun; Gu, Zi; Chen, Yu
    Biomaterials (2019), 211 (), 1-13CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
    A review. It is the challenging goal in cancer biomedicine to search novel cancer-therapeutic modality with concurrent high therapeutic efficiency on combating cancer and low side effects to normal cells/tissues. The recently developed nanocatalytic cancer therapy based on catalytic Fenton reaction represents one of the promising paradigms for potential clin. translation, which has got fast progress very recently. This progress report discusses the rational design and fabrication of Fenton reaction-based nanocatalysts for triggering the in-situ Fenton chem. reaction within tumor microenvironment to generate highly toxic hydroxyl radicals (•OH), which is highly efficient for killing the cancer cells and suppressing the tumor growth. Several strategies for optimizing the nanocatalytic cancer-therapeutic efficiency of Fenton reaction have been highlighted, including screening high-performance Fenton nanocatalysts, increasing peroxide-hydrogen amts. as the reactants, changing the Fenton-reaction conditions (e.g., temp., acidity and photo-triggering), and Fenton reaction-based synergistic cancer therapy such as some sequential nanocatalytic reactions with improved therapeutic outcome. The facing challenges and future developments of Fenton reaction-based nanocatalytic cancer therapy are also discussed for further promoting the clin. translation of this emerging cancer-therapeutic modality to benefit the cancer patients.
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    Halliwell, B.; Clement, M. V.; Long, L. H. Hydrogen Peroxide in the Human Body. FEBS Lett. 2000, 486 (1), 10– 13,  DOI: 10.1016/S0014-5793(00)02197-9
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    Hydrogen peroxide in the human body
    Halliwell, B.; Clement, M. V.; Long, L. H.
    FEBS Letters (2000), 486 (1), 10-13CODEN: FEBLAL; ISSN:0014-5793. (Elsevier Science B.V.)
    A review with 89 refs. Hydrogen peroxide (H2O2) is widely regarded as a cytotoxic agent whose levels must be minimized by the action of antioxidant defense enzymes. In fact, H2O2 is poorly reactive in the absence of transition metal ions. Exposure of certain human tissues to H2O2 may be greater than is commonly supposed: substantial amts. of H2O2 can be present in beverages commonly drunk (esp. instant coffee), in freshly voided human urine, and in exhaled air. Levels of H2O2 in the human body may be controlled not only by catabolism but also by excretion, and H2O2 could play a role in the regulation of renal function and as an antibacterial agent in the urine. Urinary H2O2 levels are influenced by diet, but under certain conditions might be a valuable biomarker of 'oxidative stress'.
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    Production of large amounts of hydrogen peroxide by human tumor cells
    Szatrowski, Ted P.; Nathan, Carl F.
    Cancer Research (1991), 51 (3), 794-8CODEN: CNREA8; ISSN:0008-5472.
    Few nonphagocytic cells are known to generate reactive oxygen intermediates. Based on horseradish peroxidase-dependent, catalase-inhibitable oxidn. of fluorescent scopoletin, seven human tumor cell lines constitutively elaborated H2O2 at rates (up to 0.5 nmol/104) cells/h) large enough that cumulative amts. at 4 h were comparable to the amt. of H2O2 produced by phorbol ester-triggered neutrophils. Superoxide dismutase-inhibitable ferricytochrome c redn. was detectable at much lower rates. H2O2 prodn. was inhibited by diphenyleneiodonium, a flavoprotein binder (concn. producing 50% inhibition, 0.3 μM), and diethyldithiocarbamate, a divalent cation chelator (concn. producing 50% inhibition, 3 μM), but not by cyanide or azide, inhibitors of electron transport, or by agents that inhibit xanthine oxidase, polyamine oxidase, or cytochrome P 450. Cytochrome b559, present in human phagocytes and lymphocytes, was undetectable in these tumor cells by a sensitive spectrophotometric method. Mouse fibroblasts transfected with human tyrosinase cDNA made melanin, but not H2O2. Constitutive generation of large amts. of reactive oxygen intermediates, if it occurs in vivo, might contribute to the ability of some tumors to mutate, inhibit antiproteases, injure local tissues, and therefore promote tumor heterogeneity, invasion, and metastasis.
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    Kim, J.; Cho, H. R.; Jeon, H.; Kim, D.; Song, C.; Lee, N.; Choi, S. H.; Hyeon, T. Continuous O2-Evolving MnFe2O4 Nanoparticle-Anchored Mesoporous Silica Nanoparticles for Efficient Photodynamic Therapy in Hypoxic Cancer. J. Am. Chem. Soc. 2017, 139 (32), 10992– 10995,  DOI: 10.1021/jacs.7b05559
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    Continuous O2-Evolving MnFe2O4 Nanoparticle-Anchored Mesoporous Silica Nanoparticles for Efficient Photodynamic Therapy in Hypoxic Cancer
    Kim, Jonghoon; Cho, Hye Rim; Jeon, Hyejin; Kim, Dokyoon; Song, Changyeong; Lee, Nohyun; Choi, Seung Hong; Hyeon, Taeghwan
    Journal of the American Chemical Society (2017), 139 (32), 10992-10995CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Therapeutic effects of photodynamic therapy (PDT) are limited by cancer hypoxia because the PDT process is dependent on O2 concn. Herein, we design biocompatible manganese ferrite nanoparticle-anchored mesoporous silica nanoparticles (MFMSNs) to overcome hypoxia, consequently enhancing the therapeutic efficiency of PDT. By exploiting the continuous O2-evolving property of MnFe2O4 nanoparticles through the Fenton reaction, MFMSNs relieve hypoxic condition using a small amt. of nanoparticles and improve therapeutic outcomes of PDT for tumors in vivo. In addn., MFMSNs exhibit T2 contrast effect in magnetic resonance imaging (MRI), allowing in vivo tracking of MFMSNs. These findings demonstrate great potential of MFMSNs for theranostic agents in cancer therapy.
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    Peng, Y.; Wang, Z.; Liu, W.; Zhang, H.; Zuo, W.; Tang, H.; Chen, F.; Wang, B. Size- and Shape-Dependent Peroxidase-like Catalytic Activity of MnFe2O4 Nanoparticles and Their Applications in Highly Efficient Colorimetric Detection of Target Cancer Cells. Dalt. Trans. 2015, 44 (28), 12871– 12877,  DOI: 10.1039/C5DT01585E
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    Size- and shape-dependent peroxidase-like catalytic activity of MnFe2O4 Nanoparticles and their applications in highly efficient colorimetric detection of target cancer cells
    Peng, Yunhua; Wang, Zhiyi; Liu, Weisheng; Zhang, Haoli; Zuo, Wei; Tang, Huiang; Chen, Fengjuan; Wang, Baodui
    Dalton Transactions (2015), 44 (28), 12871-12877CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
    The catalytic activity of nanocrystal catalysts depends strongly on their chem. compn., size, and shape. Herein, the authors report four different sizes and shapes of MnFe2O4 nanoparticles (NPs) prepd. by a hydrothermal procedure. In addn., the size- and shape-dependent peroxidase-like activity of these NPs was first explored using 3,3',5,5'-tetramethyl-benzidine and H2O2 as peroxidase substrates. The peroxidase-like activities of the MnFe2O4 NPs were size- and shape-dependent and followed the order of 4 nm (spherical) > 18 nm (plate-like) > 27 nm (near-cubic) > 16 nm (spherical); this order was closely related to their surface-to-vol. ratio and atom arrangements. Such a study is of great significance for peroxidase nanomimetics with enhanced activity and use. Furthermore, folic acid (FA)-conjugated MnFe2O4 NPs allow the detection of folate receptor-rich cancer cells. Such study can be widely used for the identification of important target mols.
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    Fu, J.; Shao, Y.; Wang, L.; Zhu, Y. Lysosome-Controlled Efficient ROS Overproduction against Cancer Cells with a High PH-Responsive Catalytic Nanosystem. Nanoscale 2015, 7 (16), 7275– 7283,  DOI: 10.1039/C5NR00706B
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    Lysosome-controlled efficient ROS overproduction against cancer cells with a high pH-responsive catalytic nanosystem
    Fu, Jingke; Shao, Yiran; Wang, Liyao; Zhu, Yingchun
    Nanoscale (2015), 7 (16), 7275-7283CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
    Excess reactive oxygen species (ROS) have been proved to damage cancer cells efficiently. ROS overprodn. is thus greatly desirable for cancer therapy. To date, ROS prodn. is generally uncontrollable and outside cells, which always bring severe side-effects in the vasculature. Since most ROS share a very short half-life and primarily react close to their site of formation, it would be more efficient if excess ROS are controllably produced inside cancer cells. Herein, we report an efficient lysosome-controlled ROS overprodn. via a pH-responsive catalytic nanosystem (FeOx-MSNs), which catalyze the decompn. of H2O2 to produce considerable ROS selectively inside the acidic lysosomes (pH 5.0) of cancer cells. After a further incorporation of ROS-sensitive TMB into the nanosystem (FeOx-MSNs-TMB), both a distinct cell labeling and an efficient death of breast carcinoma cells are obtained. This lysosome-controlled efficient ROS overprodn. suggests promising applications in cancer treatments.
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    He, W.; Zhou, Y. T.; Wamer, W. G.; Boudreau, M. D.; Yin, J. J. Mechanisms of the PH Dependent Generation of Hydroxyl Radicals and Oxygen Induced by Ag Nanoparticles. Biomaterials 2012, 33 (30), 7547– 7555,  DOI: 10.1016/j.biomaterials.2012.06.076
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    Mechanisms of the pH dependent generation of hydroxyl radicals and oxygen induced by Ag nanoparticles
    He, Weiwei; Zhou, Yu-Ting; Wamer, Wayne G.; Boudreau, Mary D.; Yin, Jun-Jie
    Biomaterials (2012), 33 (30), 7547-7555CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
    Many of the chem. and biol. effects of silver nanoparticles (Ag NPs) are attributed to the generation of reactive oxygen species (ROS). ESR spectroscopy was used to provide direct evidence for generating ROS during decompn. of H2O2 assisted by Ag NPs. Hydroxyl radical formation was obsd. under acidic conditions and was accompanied by dissoln. of Ag NPs. In contrast, evolution of O2 was obsd. in alk. solns. contg. H2O2 and Ag NPs; however, no net dissoln. of Ag NPs was obsd. due to re-redn. of Ag+ as evidenced by a cyclic reaction. Since H2O2 is a biol. relevant product being continuously generated in cells, these results obtained under conditions mimicking different biol. microenvironments may provide insights for finding new biomedical applications for Ag NPs and for risk assessment.
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    Maji, S. K.; Mandal, A. K.; Nguyen, K. T.; Borah, P.; Zhao, Y. Cancer Cell Detection and Therapeutics Using Peroxidase-Active Nanohybrid of Gold Nanoparticle-Loaded Mesoporous Silica-Coated Graphene. ACS Appl. Mater. Interfaces 2015, 7 (18), 9807– 9816,  DOI: 10.1021/acsami.5b01758
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    Cancer Cell Detection and Therapeutics Using Peroxidase-Active Nanohybrid of Gold Nanoparticle-Loaded Mesoporous Silica-Coated Graphene
    Maji, Swarup Kumar; Mandal, Amal Kumar; Nguyen, Kim Truc; Borah, Parijat; Zhao, Yanli
    ACS Applied Materials & Interfaces (2015), 7 (18), 9807-9816CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
    Development of efficient artificial enzymes is an emerging field in nanobiotechnol., since these artificial enzymes could overcome serious disadvantages of natural enzymes. In this work, a new nanostructured hybrid was developed as a mimetic enzyme for in vitro detection and therapeutic treatment of cancer cells. The hybrid (GSF@AuNPs) was prepd. by the immobilization of gold nanoparticles (AuNPs) on mesoporous silica-coated nanosized reduced graphene oxide conjugated with folic acid, a cancer cell-targeting ligand. The GSF@AuNPs hybrid showed unprecedented peroxidase-like activity, monitored by catalytic oxidn. of a typical peroxidase substrate, 3,3',5,5'-tetramethylbenzidine (TMB), in the presence of H2O2. On basis of this peroxidase activity, the hybrid was utilized as a selective, quant., and fast colorimetric detection probe for cancer cells. Finally, the hybrid as a mimetic enzyme was employed for H2O2- and ascorbic acid (AA)-mediated therapeutics of cancer cells. In vitro expts. using human cervical cancer cells (HeLa cells) exhibited the formation of reactive oxygen species (OH• radical) in the presence of peroxidase-mimic GSF@AuNPs with either exogenous H2O2 or endogenous H2O2 generated from AA, leading to an enhanced cytotoxicity to HeLa cells. In the case of normal cells (human embryonic kidney HEK 293 cells), the treatment with the hybrid and H2O2 or AA showed no obvious damage, proving selective killing effect of the hybrid to cancer cells.
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    Chen, Z.; Yin, J. J.; Zhou, Y. T.; Zhang, Y.; Song, L.; Song, M.; Hu, S.; Gu, N. Dual Enzyme-like Activities of Iron Oxide Nanoparticles and Their Implication for Diminishing Cytotoxicity. ACS Nano 2012, 6 (5), 4001– 4012,  DOI: 10.1021/nn300291r
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    Dual Enzyme-like Activities of Iron Oxide Nanoparticles and Their Implication for Diminishing Cytotoxicity
    Chen, Zhongwen; Yin, Jun-Jie; Zhou, Yu-Ting; Zhang, Yu; Song, Lina; Song, Mengjie; Hu, Sunling; Gu, Ning
    ACS Nano (2012), 6 (5), 4001-4012CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    Iron oxide nanoparticles (IONPs) are frequently used in biomedical applications, yet their toxic potential is still a major concern. While most studies of biosafety focus on cellular responses after exposure to nanomaterials, little is reported to analyze reactions on the surface of nanoparticles as a source of cytotoxicity. Here we report that different intracellular microenvironment in which IONPs are located leads to contradictive outcomes in their abilities to produce free radicals. We first verified pH-dependent peroxidase-like and catalase-like activities of IONPs and investigated how they interact with hydrogen peroxide (H2O2) within cells. Results showed that IONPs had a concn.-dependent cytotoxicity on human glioma U251 cells, and they could enhance H2O2-induced cell damage dramatically. By conducting ESR spectroscopy expts., we showed that both Fe3O4 and γ-Fe2O3 nanoparticles could catalyze H2O2 to produce hydroxyl radicals in acidic lysosome mimic conditions, with relative potency Fe3O4 > γ-Fe2O3, which was consistent with their peroxidase-like activities. However, no hydroxyl radicals were obsd. in neutral cytosol mimic conditions with both nanoparticles. Instead, they decompd. H2O2 into H2O and O2 directly in this condition through catalase-like activities. Transmission electron micrographs revealed that IONPs located in lysosomes in cells, the acidic environment of which may contribute to hydroxyl radical prodn. This is the first study regarding cytotoxicity based on their enzyme-like activities. Since H2O2 is continuously produced in cells, our data indicate that lysosome-escaped strategy for IONP delivery would be an efficient way to diminish long-term toxic potential.
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    Zhang, C.; Bu, W.; Ni, D.; Zhang, S.; Li, Q.; Yao, Z.; Zhang, J.; Yao, H.; Wang, Z.; Shi, J. Synthesis of Iron Nanometallic Glasses and Their Application in Cancer Therapy by a Localized Fenton Reaction. Angew. Chem., Int. Ed. 2016, 55 (6), 2101– 2106,  DOI: 10.1002/anie.201510031
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    Synthesis of Iron Nanometallic Glasses and Their Application in Cancer Therapy by a Localized Fenton Reaction
    Zhang, Chen; Bu, Wenbo; Ni, Dalong; Zhang, Shenjian; Li, Qing; Yao, Zhenwei; Zhang, Jiawen; Yao, Heliang; Wang, Zheng; Shi, Jianlin
    Angewandte Chemie, International Edition (2016), 55 (6), 2101-2106CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Metallic glasses and cancer theranostics are emerging fields that do not seem to be related to each other. Herein, we report the facile synthesis of amorphous iron nanoparticles (AFeNPs) and their superior physicochem. properties compared to their cryst. counterpart, iron nanocrystals (FeNCs). The AFeNPs can be used for cancer theranostics by inducing a Fenton reaction in the tumor by taking advantage of the mild acidity and the overproduced H2O2 in a tumor microenvironment: Ionization of the AFeNPs enables on-demand ferrous ion release in the tumor, and subsequent H2O2 disproportionation leads to efficient .OH generation. The endogenous stimuli-responsive .OH generation in the presence AFeNPs enables a highly specific cancer therapy without the need for external energy input.
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    Li, W. P.; Su, C. H.; Chang, Y. C.; Lin, Y. J.; Yeh, C. S. Ultrasound-Induced Reactive Oxygen Species Mediated Therapy and Imaging Using a Fenton Reaction Activable Polymersome. ACS Nano 2016, 10 (2), 2017– 2027,  DOI: 10.1021/acsnano.5b06175
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    50
    Ultrasound-Induced Reactive Oxygen Species Mediated Therapy and Imaging Using a Fenton Reaction Activable Polymersome
    Li, Wei-Peng; Su, Chia-Hao; Chang, Yi-Ching; Lin, Yu-Jiung; Yeh, Chen-Sheng
    ACS Nano (2016), 10 (2), 2017-2027CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    Ultrasound techniques have been extensively employed for diagnostic purposes. Because of its features of low cost, easy access, and noninvasive real-time imaging, toward clin. practice it is highly anticipated to simply use diagnostic ultrasound to concurrently perform imaging and therapy. We report a H2O2-filled polymersome to display echogenic reflectivity and reactive oxygen species-mediated cancer therapy simply triggered by the microultrasound diagnostic system accompanied by MR imaging. Instead of filling common perfluorocarbons, the encapsulation of H2O2 in H2O2/Fe3O4-PLGA polymersome provides O2 as the echogenic source and •OH as the therapeutic element. On exposure to ultrasound, the polymersome can be easily disrupted to yield •OH through the Fenton reaction by reaction of H2O2 and Fe3O4. We showed that malignant tumors can be completely removed in a nonthermal process.
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    He, Y.; Del Valle, A.; Qian, Y.; Huang, Y. F. Near Infrared Light-Mediated Enhancement of Reactive Oxygen Species Generation through Electron Transfer from Graphene Oxide to Iron Hydroxide/Oxide. Nanoscale 2017, 9 (4), 1559– 1566,  DOI: 10.1039/C6NR08784A
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    Near infrared light-mediated enhancement of reactive oxygen species generation through electron transfer from graphene oxide to iron hydroxide/oxide
    He, Yue; del Valle, Andrea; Qian, Yu; Huang, Yu-Fen
    Nanoscale (2017), 9 (4), 1559-1566CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
    Clin. applications of current photodynamic therapy (PDT) agents are often restricted to be activated only by UV and visible light, which have very poor tissue penetration depths. In this study, a new near IR (NIR)-absorbing nanoagent based on graphene oxide decorated with iron hydroxide/oxide (GO-FeOxH) was developed for light-activated nanomaterial-mediated PDT. This nanocomposite, GO-FeOxH was prepd. via the one-step electrooxidn. of iron nails in an aq. GO soln. The as-prepd. GO-FeOxH showed a much higher reactive oxygen species (ROS) activity under NIR light irradn. than GO. Through a variety of spectroscopic analyses, the mechanism involved in the enhancement of ROS activity of GO by FeOxH was systematically investigated. We obsd. that NIR light irradn. promotes electron transfer from GO to the Fe(III) of FeOxH and accelerates their reaction with O2, forming superoxide anion radicals, which then undergo a disproportionation reaction to produce H2O2. H2O2 then reacts with Fe(II) in FeOxH to mediate Fenton reactions, producing amplified hydroxyl radicals. Using in vitro studies, we demonstrated that GO-FeOxH can be used as a NIR activatable PDT nanoagent, providing efficient cancer therapy.
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  52. 52
    Ranji-Burachaloo, H.; Gurr, P. A.; Dunstan, D. E.; Qiao, G. G. Cancer Treatment through Nanoparticle-Facilitated Fenton Reaction. ACS Nano 2018, 12 (12), 11819– 11837,  DOI: 10.1021/acsnano.8b07635
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    52
    Cancer Treatment through Nanoparticle-Facilitated Fenton Reaction
    Ranji-Burachaloo, Hadi; Gurr, Paul A.; Dunstan, Dave E.; Qiao, Greg G.
    ACS Nano (2018), 12 (12), 11819-11837CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    A review. Currently, cancer is the second largest cause of death worldwide and has reached crit. levels. In spite of all the efforts, common treatments including chemotherapy, photodynamic therapy, and photothermal therapy suffer from various problems which limit their efficiency and performance. For this reason, different strategies are being explored which improve the efficiency of these traditional therapeutic methods or treat the tumor cells directly. One such strategy utilizing the Fenton reaction has been investigated by many groups for the possible treatment of cancer cells. This approach is based on the knowledge that high levels of hydrogen peroxide exist within cancer cells and can be used to catalyze the Fenton reaction, leading to cancer-killing reactive oxygen species. Anal. of the current literature has shown that, due to the diverse morphologies, different sizes, various chem. properties, and the tunable structure of nanoparticles, nanotechnol. offers the most promising method to facilitate the Fenton reaction with cancer therapy. This review aims to highlight the use of the Fenton reaction using different nanoparticles to improve traditional cancer therapies and the emerging Fenton-based therapy, highlighting the obstacles, challenges, and promising developments in each of these areas.
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    Bokare, A. D.; Choi, W. Review of Iron-Free Fenton-like Systems for Activating H2O2 in Advanced Oxidation Processes. J. Hazard. Mater. 2014, 275, 121– 135,  DOI: 10.1016/j.jhazmat.2014.04.054
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    Review of iron-free Fenton-like systems for activating H2O2 in advanced oxidation processes
    Bokare, Alok D.; Choi, Wonyong
    Journal of Hazardous Materials (2014), 275 (), 121-135CODEN: JHMAD9; ISSN:0304-3894. (Elsevier B.V.)
    A review is given. Fe-catalyzed H2O2 decompn. for in situ generation of hydroxyl radicals (HO•) has been extensively developed as advanced oxidn. processes (AOPs) for environmental applications. A variety of catalytic iron species constituting metal salts (in Fe2+ or Fe3+ form), metal oxides (e.g., Fe2O3, Fe3O4), and zero-valent metal (Fe0) have been exploited for chem. (classical Fenton), photochem. (photo-Fenton) and electrochem. (electro-Fenton) degrdn. pathways. However, the requirement of strict acidic conditions to prevent iron pptn. still remains the bottleneck for iron-based AOPs. We present a review of alternative non-Fe Fenton catalysts and their reactivity towards H2O2 activation. Elements with multiple redox states (such as Cr, Ce, Cu, Co, Mn and Ru) all directly decomp. H2O2 into HO• through conventional Fenton-like pathways. The in situ formation of H2O2 and decompn. into HO• can be also achieved using electron transfer mechanism in 0-valent Al/O system. Although these Fenton systems (except Al) work efficiently even at neutral pH, the H2O2 activation mechanism is very specific to the nature of the catalyst and critically depends on its compn. This paper describes the complex mechanisms and emphasizes on practical limitations influencing their environmental applications.
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    Wu, D.; Gao, Y.; Qi, Y.; Chen, L.; Ma, Y.; Li, Y. Peptide-Based Cancer Therapy: Opportunity and Challenge. Cancer Lett. 2014, 351 (1), 13– 22,  DOI: 10.1016/j.canlet.2014.05.002
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    Peptide-based cancer therapy: Opportunity and challenge
    Wu, Dongdong; Gao, Yanfeng; Qi, Yuanming; Chen, Lixiang; Ma, Yuanfang; Li, Yanzhang
    Cancer Letters (New York, NY, United States) (2014), 351 (1), 13-22CODEN: CALEDQ; ISSN:0304-3835. (Elsevier)
    A review. Cancer is one of the leading causes of death worldwide. Conventional cancer therapies mainly focus on mass cell killing without high specificity and often cause severe side effects and toxicities. Peptides are a novel class of anticancer agents that could specifically target cancer cells with lower toxicity to normal tissues, which will offer new opportunities for cancer prevention and treatment. Anticancer peptides face several therapeutic challenges. In this review, we present the sources and mechanisms of anticancer peptides and further discuss modification strategies to improve the anticancer effects of bioactive peptides.
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    Qi, G.-B.; Gao, Y.-J.; Wang, L.; Wang, H. Self-Assembled Peptide-Based Nanomaterials for Biomedical Imaging and Therapy. Adv. Mater. 2018, 30 (22), 1703444,  DOI: 10.1002/adma.201703444
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    Qiao, Z. Y.; Lin, Y. X.; Lai, W. J.; Hou, C. Y.; Wang, Y.; Qiao, S. L.; Zhang, D.; Fang, Q. J.; Wang, H. A General Strategy for Facile Synthesis and in Situ Screening of Self-Assembled Polymer-Peptide Nanomaterials. Adv. Mater. 2016, 28 (9), 1859– 1867,  DOI: 10.1002/adma.201504564
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    A general strategy for facile synthesis and in situ screening of self-assembled polymer-peptide nanomaterials
    Qiao, Zeng-Ying; Lin, Yao-Xin; Lai, Wen-Jia; Hou, Chun-Yuan; Wang, Yi; Qiao, Sheng-Lin; Zhang, Di; Fang, Qiao-Jun; Wang, Hao
    Advanced Materials (Weinheim, Germany) (2016), 28 (9), 1859-1867CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The authors first report a general strategy for facile synthesis and in situs screening of a library of self-assembled polymer-peptide conjugates (PPCs). The high-yield, bio-freiendly chem., and mild reaction conditions fabricate the combinatorial synthesis and screening of therapeutic peptide nanomaterials. The PPCs could self-assemble into nanoparticles in the reaction process and were directly used for cytotoxicy assay without further purifn. This strategy fabricated investigating structure-function relationships of PPC library, and PPCs with optimal structures were prepd. according to the guidelines. The reliability and scalability of this strategy were proved by enhanced cancer therapeutic efficacy in vitro and in vivo. Therefore, the facile approach opened an avenue for rapid synthesis and screening of peptide nanomaterials. By further developing this synthesis and screening approach to incorporate other functional peptides and stimuli sensitive spacers, novel peptide nanomaterials may be found, which have broad application in disease diagnosis and therapy.
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    Wang, Y.; Lin, Y.-X.; Qiao, Z.-Y.; An, H.-W.; Qiao, S.-L.; Wang, L.; Rajapaksha, R. P. Y. J.; Wang, H. Self-Assembled Autophagy-Inducing Polymeric Nanoparticles for Breast Cancer Interference In-Vivo. Adv. Mater. 2015, 27 (16), 2627– 2634,  DOI: 10.1002/adma.201405926
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    Self-assembled autophagy-inducing polymeric nanoparticles for breast cancer interference in-vivo
    Wang, Yi; Lin, Yao-Xin; Qiao, Zeng-Ying; An, Hong-Wei; Qiao, Sheng-Lin; Wang, Lei; Rajapaksha, R. P. Yeshan J.; Wang, Hao
    Advanced Materials (Weinheim, Germany) (2015), 27 (16), 2627-2634CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The authors demonstrated a convenient approach to prepg. self-assembled micelle-like nanoparticles composed of pH-sensitive poly(β-amino ester)s and an autophagy-inducing peptide (Bec1). The P-Bec1 nanoparticles displayed enhanced autophagy-inducing cytotoxicity to MCF-7 cells that are Bec1 deficient, because P-Bec1 can contribute to efficient internalization of the Bec1 peptide into cells by the endocytosis pathway. Moreover, the P-Bec1 nanoparticles effectively induced autophagy and inhibited tumor growth. By modulating the Bec1 peptide autophagy-inducing effect assisted by pH-sensitive polymers, it was identified that the autophagy anticancer efficiency of P-Bec1. It is believed that the P-Bec1 peptide described here provides an important addn. to existing efforts in identifying new cancer therapies, and has a promising effect esp. in autophagy deficiency tumors.
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    Prives, C. Signaling to P53: Breaking Minireview the MDM2–P53 Circuit. Cell 1998, 95 (1), 5– 8,  DOI: 10.1016/S0092-8674(00)81774-2
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    Signaling to p53: breaking the MDM2-p53 circuit
    Prives, Carol
    Cell (Cambridge, Massachusetts) (1998), 95 (1), 5-8CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    A review, with 27 refs. Current knowledge suggests that diverse upstream signals funnel into a single crit. interaction, namely that between p53 and its neg. regulator, MDM2. The author discusses p53 interactions with MDM2, signaling through covalent modification of p53, the discovery of ARF explaining how oncogenes regulate p53, the complexity of p53 circuitry, and future directions of research.
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    Frappier, V.; Duran, M.; Keating, A. E. PixelDB: Protein–Peptide Complexes Annotated with Structural Conservation of the Peptide Binding Mode. Protein Sci. 2018, 27 (1), 276– 285,  DOI: 10.1002/pro.3320
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    PixelDB: Protein-peptide complexes annotated with structural conservation of the peptide binding mode
    Frappier, Vincent; Duran, Madeleine; Keating, Amy E.
    Protein Science (2018), 27 (1), 276-285CODEN: PRCIEI; ISSN:1469-896X. (Wiley-Blackwell)
    PixelDB, the Peptide Exosite Location Database, compiles 1966 non-redundant, high-resoln. structures of protein-peptide complexes filtered to minimize the impact of crystal packing on peptide conformation. The database is organized to facilitate study of structurally conserved vs. non-conserved elements of protein-peptide engagement. PixelDB clusters complexes based on the structural similarity of the peptide-binding protein, and by comparing complexes within a cluster highlights examples of domains that engage peptides using more than one binding mode. PixelDB also identifies conserved peptide core structural motifs characteristic of each binding mode. Peptide regions that flank core motifs often make non-structurally conserved interactions with the protein surface in regions we call exosites. Many examples establish that exosite contacts can be important for enhancing protein binding and interaction specificity. PixelDB provides a resource for computational and structural biologists to study, model, and predict core-motif and exosite-contacting peptide interactions. PixelDB is available to the community without restriction in a convenient flat-file format with accompanying visualization tools.
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    Yan, J.; He, W.; Yan, S.; Niu, F.; Liu, T.; Ma, B.; Shao, Y.; Yan, Y.; Yang, G.; Lu, W.; Du, Y.; Lei, B.; Ma, P. X. Self-Assembled Peptide-Lanthanide Nanoclusters for Safe Tumor Therapy: Overcoming and Utilizing Biological Barriers to Peptide Drug Delivery. ACS Nano 2018, 12 (2), 2017– 2026,  DOI: 10.1021/acsnano.8b00081
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    60
    Self-Assembled Peptide-Lanthanide Nanoclusters for Safe Tumor Therapy: Overcoming and Utilizing Biological Barriers to Peptide Drug Delivery
    Yan, Jin; He, Wangxiao; Yan, Siqi; Niu, Fan; Liu, Tianya; Ma, Bohan; Shao, Yongping; Yan, Yuwei; Yang, Guang; Lu, Wuyuan; Du, Yaping; Lei, Bo; Ma, Peter X.
    ACS Nano (2018), 12 (2), 2017-2026CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    Developing a sophisticated nanomedicine platform to deliver therapeutics effectively and safely into tumor/cancer cells remains challenging in the field of nanomedicine. In particular, reliable peptide drug delivery systems capable of overcoming biol. barriers are still lacking. Here, we developed a simple, rapid, and robust strategy to manuf. nanoclusters of ∼90 nm in diam. that are self-assembled from lanthanide-doped nanoparticles (5 nm), two anticancer peptides with different targets (BIM and PMI), and one cyclic peptide iNGR targeted to cancer cells. The peptide-lanthanide nanoclusters (LDC-PMI-BIM-iNGR) enhanced the resistance of peptide drugs to proteolysis, disassembled in response to reductive conditions that are present in the tumor microenvironment and inhibited cancer cell growth in vitro and in vivo. Notably, LDC-PMI-BIM-iNGR exhibited extremely low systemic toxicity and side effects in vivo. Thus, the peptide-lanthanide nanocluster may serve as an ideal multifunctional platform for safe, targeted, and efficient peptide drug delivery in cancer therapy.
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    Tuguntaev, R. G.; Chen, S.; Eltahan, A. S.; Mozhi, A.; Jin, S.; Zhang, J.; Li, C.; Wang, P. C.; Liang, X.-J. P-Gp Inhibition and Mitochondrial Impairment by Dual-Functional Nanostructure Based on Vitamin E Derivatives To Overcome Multidrug Resistance. ACS Appl. Mater. Interfaces 2017, 9 (20), 16900– 16912,  DOI: 10.1021/acsami.7b03877
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    61
    P-gp Inhibition and Mitochondrial Impairment by Dual-Functional Nanostructure Based on Vitamin E Derivatives To Overcome Multidrug Resistance
    Tuguntaev, Ruslan G.; Chen, Shizhu; Eltahan, Ahmed Shaker; Mozhi, Anbu; Jin, Shubin; Zhang, Jinchao; Li, Chan; Liang, Xing-Jie
    ACS Applied Materials & Interfaces (2017), 9 (20), 16900-16912CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
    Vitamin E derivs. possess many essential features for drug-delivery applications, such as biocompatibility, stability, improvement of water soly. of hydrophobic compds., anticancer activity, and the ability to overcome multidrug resistance (MDR). Herein, vitamin E derivs. are used to overcome MDR through a combined P-glycoprotein (P-gp) inhibition and mitochondrial impairment strategy. A novel nanomicellar drug-delivery system as a carrier for doxorubicin (DOX) was developed, in which D-α-tocopheryl polyethylene glycol 1000 succinate was used as a P-gp inhibitor, α-tocopheryl succinate was introduced as a mitochondrial disrupting agent, and D-α-tocopheryl polyethylene glycol 2000 succinate was used as the main building block of micelles. The optimal ratio between the components of the nanocarrier was detd. The resultant DOX-loaded mixed micelles exhibited a suitable size of 52.08 nm, high drug-loading encapsulation efficiency (>98%), high stability, and pH-dependent drug release. In vitro expts. demonstrated a significantly increased cytotoxic activity of DOX-loaded mixed micelles against resistant MCF-7/Adr cells (45-fold higher than DOX after 48 h of treatment). In vivo studies revealed superior antitumor efficiency with less cardio- and hepatotoxicities of DOX-loaded micelles compared with that of free DOX. These results highlight that the developed DOX-loaded mixed micelles have a promising potential to overcome MDR in chemotherapy for clin. usage.
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    MMP2-Sensitive PEG-Lipid Copolymers: A New Type of Tumor-Targeted P-Glycoprotein Inhibitor
    Dai, Zhi; Yao, Qing; Zhu, Lin
    ACS Applied Materials & Interfaces (2016), 8 (20), 12661-12673CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
    Low tumor targetability and multidrug resistance (MDR) are two major impediments to the success of cancer treatments. Nanomaterials which possess high tumor targetability and the ability to reverse the MDR are rare. This report describes a new type of self-assembling polyethylene glycol-phosphoethanolamine-based copolymers (PEG-pp-PE) which showed both the matrix metalloproteinase 2 (MMP2)-sensitive tumor-targeted drug delivery and ability to inhibit the P-glycoprotein (P-gp)-mediated drug efflux. In this study, we synthesized a series of the homologous analogs of PEG-pp-PE copolymers and investigated the influence of their structures, including PEG lengths and peptide linkers, on the drug efflux, and identified the underlying mechanisms. We found that the whole structure (PEG-peptide-lipid) rather than any parts of the copolymers was key for the P-gp inhibition and a delicate balance between the hydrophilic and lipophilic segments of the PEG-pp-PE copolymers was needed for better modulating the P-gp-mediated drug efflux. The best copolymer, PEG2k-pp-PE, showed even higher P-gp inhibition effect than the D-α-tocopherol polyethylene glycol 1000 succinate (TPGS1k). We also found that the P-gp inhibition capability of PEG-pp-PE copolymers was highly assocd. with the P-gp down-regulation, the increase in the plasma membrane fluidity, and the inhibition of the P-gp ATPase activity. Besides, the excellent physicochem. properties, high drug loading, MMP2-dependent drug release, and improved drug efficacy in the MDR cancer cells suggested that the PEG-pp-PE copolymers might have great potential for building tumor-targeted drug delivery systems for treating drug-resistant cancers.
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    Emerging advances in P-glycoprotein inhibitory nanomaterials for drug delivery
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    A review. : P-glycoprotein 1 (P-gp) pumps out many foreign/toxic substances out of the cells, including intracellular drugs, causing multidrug resistance (MDR) and chemotherapy failure. It remains quite a challenge to inhibit P-gp to combat MDR and improve cellular bioavailability since it requires efficient inhibitors along with adequate formulation strategy. Lately, nanocarriers are gaining much attention and form an attractive platform for delivering drugs into cells. Therefore, nanomaterials act as direct inhibitors of P-gp will be an attractive alternative to overcome MDR.: This paper reviews the most recent advances on those nanomaterials that are currently in the developmental stage and has proven useful to treat P-gp involved MDR. Also, we emphasize those emerging multifunctional nanomaterials that can construct 'smart' carriers for both tumor targeting and P-gp inhibition. Furthermore, the mechanisms behind P-gp inhibition and the nanoformulation strategies for drug delivery are also discussed.: In light of these updated reports, this review here seeks to suggest an alternative for the chemoresistant cases, and also bring about new thoughts on tackling P-gp concerned drug delivery issues. New advances in nanomaterials with P-gp inhibition are expected to broaden nanopharmaceutics and traditional chemotherapy applications in the coming years.
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    Li, D.; Hu, X.; Zhang, S. Biodegradation of Graphene-Based Nanomaterials in Blood Plasma Affects Their Biocompatibility, Drug Delivery, Targeted Organs and Antitumor Ability. Biomaterials 2019, 202, 12– 25,  DOI: 10.1016/j.biomaterials.2019.02.020
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    Biodegradation of graphene-based nanomaterials in blood plasma affects their biocompatibility, drug delivery, targeted organs and antitumor ability
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    Biomaterials (2019), 202 (), 12-25CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
    The extensive use of graphene-family nanomaterials (GFNs) in biomedicine and other fields has intentionally or unintentionally resulted in their introduction into the blood circulation system, but the effects of the biotransformation of GFNs in blood plasma on their biocompatibility, organ targeting, drug delivery and antitumor ability remain unclear. The present work discovered that GFN sheets were degraded in human blood plasma to holey sheets and arom. hydrocarbons. The carbon atoms connected with oxygen-contg. groups in the planes of GFNs were the initial attack sites for active substances (e.g., ·OH and O·-2) in blood plasma. Subsequently, C-C/C=C bonds were broken. The reaction rate depended strongly on the extent of oxidization of GFNs. The pristine GFNs caused secondary structure damage to proteins and disturbances of cellular metabolic pathways. In contrast, the biotransformed nanomaterials presented high biocompatibility and were located in and targeted different tissues from their pristine forms, which influenced specific organ targeting therapy. The biotransformed nanomaterials also exhibited higher efficiencies of drug delivery (drug release and location) and killing tumor cells in vitro and in vivo. These findings provide insights into the application of nanomaterials in human healthcare using biotransformed nanomaterials.
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    Platinating compounds including cisplatin, carboplatin, and oxaliplatin are common chemotherapeutic agents, however, patients developed resistance to these clinical agents after initial therapeutic treatments. Therefore, different approaches have been applied to identify novel therapeutic agents, molecular mechanisms, and targets for overcoming drug resistance. In this study, we have identified a panel of cobalt complexes that were able to specifically induce collateral sensitivity in taxol-resistant and p53-deficient cancer cells. Consistently, our reported anti-cancer functions of cobalt complexes 1-6 towards multidrug-resistant cancers have suggested the protective and non-toxic properties of cobalt metal-ions based compounds in anti-cancer therapies. As demonstrated in xenograft mouse model, our results also confirmed the identified cobalt complex 2 was able to suppress tumor growth in vivo. The anti-cancer effect of the cobalt complex 2 was further demonstrated to be exerted via the induction of autophagy, cell cycle arrest, and inhibition of cell invasion and P-glycoprotein (P-gp) activity. These data have provided alternative metal ion compounds for targeting drug resistance cancers in chemotherapies.
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    Jiang, W.; Yin, L.; Chen, H.; Paschall, A. V.; Zhang, L.; Fu, W.; Zhang, W.; Todd, T.; Yu, K. S.; Zhou, S.; Zhen, Z.; Butler, M.; Yao, L.; Zhang, F.; Shen, Y.; Li, Z.; Yin, A.; Yin, H.; Wang, X.; Avci, F. Y.; Yu, X.; Xie, J. NaCl Nanoparticles as a Cancer Therapeutic. Adv. Mater. 2019, 31 (46), 1904058,  DOI: 10.1002/adma.201904058
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    Many inorg. nanoparticles are prepd. and their behaviors in living systems are investigated. Yet, common electrolytes such as NaCl are left out of this campaign. The underlying assumption is that electrolyte nanoparticles will quickly dissolve in water and behave similarly as their constituent salts. Herein, this preconception is challenged. The study shows that NaCl nanoparticles (SCNPs) but not salts are highly toxic to cancer cells. This is because SCNPs enter cells through endocytosis, bypassing cell regulations on ion transport. When dissolved inside cancer cells, SCNPs cause a surge of osmolarity and rapid cell lysis. Interestingly, normal cells are much more resistant to the treatment due to their relatively low sodium levels. Unlike conventional chemotherapeutics, SCNPs cause immunogenic cell death or ICD. In vivo studies show that SCNPs not only kill cancer cells, but also boost an anticancer immunity. The discovery opens up a new perspective on nanoparticle-based therapeutics.
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    Intranuclear Na+, K+, and Cl- contents were measured by energy-dispersive x-ray microanal. in freeze-fractured, freeze-dried, bulk-tumor samples taken from 10 patients suffering from invasive urogenital cancers. Human biopsies were carried out during the first diagnostic interventions before any cytostatic treatment had been applied. Pathohistol. diagnosis established the malignancy in each case. The cancers were classified as keratinizing, transitional cell, or hypernephroid carcinoma. More than 250 cell nuclei were measured from each type of cancer. The results were compared with those obtained in intact human urothelium taken from patients having no malignant processes. Proximal and distal tubular epithelial cell nuclei representing the origin of human hypernephroid cancer were also measured in rat kidney because corresponding healthy human material cannot be obtained. In all 3 types of cancer cells, the av. intranuclear Na+ content was increased >3-fold and the K+ content was decreased by 32, 16, and 13%, resp. The Cl- content increased, but to a lesser extent than Na+. The intranuclear Na+:K+ ratios were >5-fold higher in the cancer cells on the av., and their distribution histograms were much broader than in the normal human urothelium and in the tubular cell nuclei of the rat kidney. Sustained depolarization of the cell membrane may have a mitogenic effect.
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    Cell & Tissue Research (2001), 304 (2), 279-285CODEN: CTSRCS; ISSN:0302-766X. (Springer-Verlag)
    In all cell types, the maintenance of normal cell vol. is an essential homeostatic function. Relatively little is known about the induction of apoptosis by hyperosmotic stress and its mol. mechanism in terminally differentiated cardiac myocytes. We compared the apoptotic response of cultured neonatal rat cardiomyoctes to hyperosmotic stress by sorbitol (SOR) with those induced by doxorubicin (Doxo) or angiotensin II (Ang II). We also examd. the apoptotic-signaling pathway stimulated by the hyperosmotic stress. Apoptosis was assessed by the observation of: (1) cell viability, (2) DNA fragmentation detected by the TUNEL method and by agarose gel electrophoresis, and (3) poly(ADP-ribose)polymerase (PARP) degrdn., and Bcl-XS and Bcl-XL levels by Western blot anal. Exposure of cardiomyocytes to 0.3 M SOR for 24 h resulted in decreased cell viability and increased generation of oligosomal DNA fragments (2.5-fold of controls). At this time, 83±5% of SOR-treated myocytes were TUNEL-pos. (vs 23.7±6.8% in controls;P<0.01). PARP levels also decreased by approx. 42% when cardiac myocytes were exposed to SOR. Hyperosmotic stress induced a more rapid and stronger apoptotic response in cardiomyocytes than Doxo or Ang II. In addn., SOR increased 3.2-fold Bcl-XS proapoptotic protein without changes in Bcl-XL antiapoptotic protein levels and in the p53-transactivating activity. Taken together, these results strongly suggest that hyperosmotic stress triggers cardiac myocyte apoptosis in a p53-independent manner, being earlier and stronger than apoptosis induced by Doxo and Ang II.
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    Poon, W.; Zhang, Y.-N.; Ouyang, B.; Kingston, B. R.; Wu, J. L. Y.; Wilhelm, S.; Chan, W. C. W. Elimination Pathways of Nanoparticles. ACS Nano 2019, 13 (5), 5785– 5798,  DOI: 10.1021/acsnano.9b01383
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    Elimination Pathways of Nanoparticles
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    ACS Nano (2019), 13 (5), 5785-5798CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    Understanding how nanoparticles are eliminated from the body is required for their successful clin. translation. Many promising nanoparticle formulations for in vivo medical applications are large (>5.5 nm) and nonbiodegradable, so they cannot be eliminated renally. A proposed pathway for these nanoparticles is hepatobiliary elimination, but their transport has not been well-studied. Here, we explored the barriers that detd. the elimination of nanoparticles through the hepatobiliary route. The route of hepatobiliary elimination is usually through the following pathway: (1) liver sinusoid, (2) space of Disse, (3) hepatocytes, (4) bile ducts, (5) intestines, and (6) out of the body. We discovered that the interaction of nanoparticles with liver nonparenchymal cells (e.g., Kupffer cells and liver sinusoidal endothelial cells) dets. the elimination fate. Each step in the route contains cells that can sequester and chem. or phys. alter the nanoparticles, which influences their fecal elimination. We showed that the removal of Kupffer cells increased fecal elimination by >10 times. Combining our results with those of prior studies, we can start to build a systematic view of nanoparticle elimination pathways as it relates to particle size and other design parameters. This is crit. to engineering medically useful and translatable nanotechnologies.
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    Biol. barriers to drug transport prevent successful accumulation of nanotherapeutics specifically at diseased sites, limiting efficacious responses in disease processes ranging from cancer to inflammation. Although substantial research efforts have aimed to incorporate multiple functionalities and moieties within the overall nanoparticle design, many of these strategies fail to adequately address these barriers. Obstacles, such as nonspecific distribution and inadequate accumulation of therapeutics, remain formidable challenges to drug developers. A reimagining of conventional nanoparticles is needed to successfully negotiate these impediments to drug delivery. Site-specific delivery of therapeutics will remain a distant reality unless nanocarrier design takes into account the majority, if not all, of the biol. barriers that a particle encounters upon i.v. administration. By successively addressing each of these barriers, innovative design features can be rationally incorporated that will create a new generation of nanotherapeutics, realizing a paradigmatic shift in nanoparticle-based drug delivery.
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    In the field of nanomedicine, gas therapy is currently a hot topic under exploration as it can treat a variety of disease conditions. The key challenge of delivering medicinal gas via any delivery system is that the technique should be feasible to deliver the gas over an appropriate time interval as well as specifically targeting the affected area. This has enabled gas therapy as an active research area with an aim to improve and discover new materials, methodologies and technologies. In this review, we present the recent advances in research on delivering medicinal gases using nanocarriers that can specifically target with precise spatial-temporal control of release behavior and discuss their future perspectives. The main emphasis has been focused on nanoparticle gas carriers to overcome the challenges in gas delivery for therapeutic applications including prevention of gas diffusion while transportation, improving the stability of the gas in the complex biol. environment, specifically targeting the tissue and controlled gas release for efficient programmed treatment modality. Furthermore, the therapeutic effects of the nanomaterial gas carriers via efficient gas releasing properties demonstrated in the preclin. studies with cell/animal models are discussed. This crit. review is intended to make clear the present status, the possibility and future advancement of gas therapy for the scientific community.
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    A quantum mech. treatment was applied to the Watson-Crick model for DNA. Since the protons are not considered as classical particles but as wave packets, the genetic proton-electron pair code cannot be 100% stable. Due to the quantummech. tunnel effect, there is always a small but finite probability that the protons will change place, alter the genetic code, and give rise to somatic mutations. The latter may be responsible for the phenomenon of aging, as well as for the occurrence of spontaneous tumors and cancer. 23 references.
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  • Abstract

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    Figure 1

    Figure 1. In vitro and in vivo effects of boron nitride nanospheres (BNs). (a) Different levels of necrosis (LDH) and apoptosis (caspase 3/7) in prostate cancer cells due to the release of boron from BA or hollow BN spheres. (b) BNS, BA, and saline effects on LNCap mouse tumor models. (c) Effect of different formulations of boron on the inhibition of tumor growth and (d) tumor volume in mice models. Reproduced with permission from ref (23). Copyright 2017 Springer Nature.

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    Figure 2

    Figure 2. A schematic illustration of intratumoral deoxygenation utilizing magnesium silicide nanoparticles (MS NPS): Reproduced with permission from ref (38). Copyright 2017 Springer Nature.

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    Figure 3

    Figure 3. Fenton chemical approach to OH· ion therapeutic systems. (a) Schematic illustration of rMOF-FA nanoparticles for cancer therapy. (b) rMOF-FA effects on HeLa and NIH-3T3 cells. (c) Peroxidase-like activity of rMOF-FA nanoparticles. (d) Synthesis scheme of rMOF-FA nanoparticles. Reproduced with permission from ref (39). Copyright 2017 American Chemical Society.

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    Figure 4

    Figure 4. Schematic diagram of peptide-based nanoclusters and their anticancer activity: (a) Graphical illustration for the construction of lanthanide-doped nanoclusters (LDC) and their cancer cell killing activity. (b) Schematic diagram of the production of small nanoparticles by the disintegration of large size nanocluster in the reducing intracellular environment. Reproduced with the permission of ref (60). Copyright 2018 American Chemical Society.

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    Figure 5

    Figure 5. P-gp inhibition by PEG-pp-PE micelles. Reproduced with permission from ref (62). Copyright 2016 American Chemical Society.

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      Kawabata, S.; Matsushita, Y.; Furuse, M.; Miyatake, S.-I.; Kuroiwa, T.; Ono, K. Clinical Study on Modified Boron Neutron Capture Therapy for Newly Diagnosed Glioblastoma. In Advances in the Biology, Imaging and Therapies for Glioblastoma; InTech, 2011; pp 325– 338.
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      There is no corresponding record for this reference.
    13. 13
      Barth, R. F.; Coderre, J. A.; Vicente, M. G. H.; Blue, T. E. Boron Neutron Capture Therapy of Cancer: Current Status and Future Prospects. Clin. Cancer Res. 2005, 11 (11), 3987– 4002,  DOI: 10.1158/1078-0432.CCR-05-0035
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      13
      Boron Neutron Capture Therapy of Cancer: Current Status and Future Prospects
      Barth, Rolf F.; Coderre, Jeffrey A.; Vicente, M. Graca H.; Blue, Thomas E.
      Clinical Cancer Research (2005), 11 (11), 3987-4002CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
      A review. Background: Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when boron-10 is irradiated with low-energy thermal neutrons to yield high linear energy transfer α particles and recoiling lithium-7 nuclei. Clin. interest in BNCT has focused primarily on the treatment of high-grade gliomas and either cutaneous primaries or cerebral metastases of melanoma, most recently, head and neck and liver cancer. Neutron sources for BNCT currently are limited to nuclear reactors and these are available in the United States, Japan, several European countries, and Argentina. Accelerators also can be used to produce epithermal neutrons and these are being developed in several countries, but none are currently being used for BNCT. Boron Delivery Agents: Two boron drugs have been used clin., sodium borocaptate (Na2B12H11SH) and a dihydroxyboryl deriv. of phenylalanine called boronophenylalanine. The major challenge in the development of boron delivery agents has been the requirement for selective tumor targeting to achieve boron concns. (∼20 μg/g tumor) sufficient to deliver therapeutic doses of radiation to the tumor with minimal normal tissue toxicity. Over the past 20 years, other classes of boron-contg. compds. have been designed and synthesized that include boron-contg. amino acids, biochem. precursors of nucleic acids, DNA-binding mols., and porphyrin derivs. High mol. wt. delivery agents include monoclonal antibodies and their fragments, which can recognize a tumor-assocd. epitope, such as epidermal growth factor, and liposomes. However, it is unlikely that any single agent will target all or even most of the tumor cells, and most likely, combinations of agents will be required and their delivery will have to be optimized. Clin. Trials: Current or recently completed clin. trials have been carried out in Japan, Europe, and the United States. The vast majority of patients have had high-grade gliomas. Treatment has consisted first of "debulking" surgery to remove as much of the tumor as possible, followed by BNCT at varying times after surgery. Sodium borocaptate and boronophenylalanine administered i.v. have been used as the boron delivery agents. The best survival data from these studies are at least comparable with those obtained by current std. therapy for glioblastoma multiforme, and the safety of the procedure has been established. Conclusions: Crit. issues that must be addressed include the need for more selective and effective boron delivery agents, the development of methods to provide semiquant. ests. of tumor boron content before treatment, improvements in clin. implementation of BNCT, and a need for randomized clin. trials with an unequivocal demonstration of therapeutic efficacy. If these issues are adequately addressed, then BNCT could move forward as a treatment modality.
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    14. 14
      Barranco, W. T.; Eckhert, C. D. Boric Acid Inhibits Human Prostate Cancer Cell Proliferation. Cancer Lett. 2004, 216 (1), 21– 29,  DOI: 10.1016/j.canlet.2004.06.001
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      14
      Boric acid inhibits human prostate cancer cell proliferation
      Barranco, Wade T.; Eckhert, Curtis D.
      Cancer Letters (Amsterdam, Netherlands) (2004), 216 (1), 21-29CODEN: CALEDQ; ISSN:0304-3835. (Elsevier B.V.)
      The role of boron in biol. includes coordinated regulation of gene expression in mixed bacterial populations and the growth and proliferation of higher plants and lower animals. Here the authors report that boric acid, the dominant form of boron in plasma, inhibits the proliferation of prostate cancer cell lines, DU-145 and LNCaP, in a dose-dependent manner. Non-tumorigenic prostate cell lines, PWR-1E and RWPE-1, and the cancer line PC-3 were also inhibited, but required concns. higher than obsd. human blood levels. Studies using DU-145 cells showed that boric acid induced a cell death-independent proliferative inhibition, with little effect on cell cycle stage distribution and mitochondrial function.
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    15. 15
      Das, B. C.; Thapa, P.; Karki, R.; Schinke, C.; Das, S.; Kambhampati, S.; Banerjee, S. K.; Van Veldhuizen, P.; Verma, A.; Weiss, L. M.; Evans, T. Boron Chemicals in Diagnosis and Therapeutics. Future Med. Chem. 2013, 5 (6), 653– 676,  DOI: 10.4155/fmc.13.38
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      15
      Boron chemicals in diagnosis and therapeutics
      Das, Bhaskar C.; Thapa, Pritam; Karki, Radha; Schinke, Caroline; Das, Sasmita; Kambhampati, Suman; Banerjee, Sushanta K.; Van Veldhuizen, Peter; Verma, Amit; Weiss, Louis M.; Evans, Todd
      Future Medicinal Chemistry (2013), 5 (6), 653-676CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)
      A review. Advances in the field of boron chem. have expanded the application of boron from material use to medicine. Boron-based drugs represent a new class of mols. that possess several biomedical applications including use as imaging agents for both optical and nuclear imaging as well as therapeutic agents with anticancer, antiviral, antibacterial, antifungal and other disease-specific activities. For example, bortezomib (Velcade), the only drug in clin. use with boron as an active element, was approved in 2003 as a proteasome inhibitor for the treatment of multiple myeloma and non-Hodgkin's lymphoma. Several other boron-based compds. are in various phases of clin. trials, which illustrates the promise of this approach for medicinal chemists working in the area of boron chem. It is expected that in the near future, several boron-contg. drugs should become available in the market with better efficacy and potency than existing drugs. This article discusses the current status of the development of boron-based compds. as diagnostic and therapeutic agents in humans.
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    16. 16
      Kane, R. C.; Bross, P. F.; Farrell, A. T.; Pazdur, R. Velcade(R): U.S. FDA Approval for the Treatment of Multiple Myeloma Progressing on Prior Therapy. Oncologist 2003, 8 (6), 508– 513,  DOI: 10.1634/theoncologist.8-6-508
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      16
      Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy
      Kane Robert C; Bross Peter F; Farrell Ann T; Pazdur Richard
      The oncologist (2003), 8 (6), 508-13 ISSN:1083-7159.
      Bortezomib (formerly PS-341), a promising new drug for the treatment of multiple myeloma, recently received accelerated approval from the U.S. Food and Drug Administration (FDA) for the therapy of patients with progressive myeloma after previous treatment. Two phase II studies of bortezomib used the same schedule of twice-weekly i.v. dosing for the first 2 weeks of each 3-week cycle. In a randomized study of 54 patients, two doses were compared (1.0 and 1.3 mg/m2) and objective responses occurred at both dose levels (23% versus 35%), including one complete response in each arm. In the other phase II study, 202 heavily pretreated patients (median of six prior therapies) all received the same schedule at 1.3 mg/m2. Of 188 evaluable patients, complete responses occurred in five (3%) and partial responses occurred in 47 (25%). The median duration of response was 365 days. The most clinically relevant adverse events were asthenic conditions, nausea, vomiting, diarrhea, thrombocytopenia, and a peripheral neuropathy that often was painful. This report highlights the FDA analysis supporting the accelerated approval.
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    17. 17
      Buac, D.; Shen, M.; Schmitt, S.; Rani Kona, F.; Deshmukh, R.; Zhang, Z.; Neslund-Dudas, C.; Mitra, B.; Dou, Q. P. From Bortezomib to Other Inhibitors of the Proteasome and Beyond. Curr. Pharm. Des. 2013, 19 (22), 4025– 4038,  DOI: 10.2174/1381612811319220012
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      17
      From bortezomib to other inhibitors of the proteasome and beyond
      Buac, Daniela; Shen, Min; Schmitt, Sara; Kona, Fathima Rani; Deshmukh, Rahul; Zhang, Zhen; Neslund-Dudas, Christine; Mitra, Bharati; Dou, Q. Ping
      Current Pharmaceutical Design (2013), 19 (22), 4025-4038CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)
      A review. The cancer drug discovery field has placed much emphasis on the identification of novel and cancer-specific mol. targets. A rich source of such targets for the design of novel anti-tumor agents is the ubiqutin-proteasome system (UP-S), a tightly regulated, highly specific pathway responsible for the vast majority of protein turnover within the cell. Because of its crit. role in almost all cell processes that ensure normal cellular function, its inhibition at one point in time was deemed non-specific and therefore not worth further investigation as a mol. drug target. However, today the proteasome is one of the most promising anti-cancer drug targets of the century. The discovery that tumor cells are in fact more sensitive to proteasome inhibitors than normal cells indeed paved the way for the design of its inhibitors. Such efforts have led to bortezomib, the first FDA approved proteasome inhibitor now used as a frontline treatment for newly diagnosed multiple myeloma (MM), relapsed/refractory MM and mantle cell lymphoma. Though successful in improving clin. outcomes for patients with hematol. malignancies, relapse often occurs in those who initially responded to bortezomib. Therefore, the acquisition of bortezomib resistance is a major issue with its therapy. Furthermore, some neuro-toxicities have been assocd. with bortezomib treatment and its efficacy in solid tumors is lacking. These observations have encouraged researchers to pursue the next generation of proteasome inhibitors, which would ideally overcome bortezomib resistance, have reduced toxicities and a broader range of anti-cancer activity. This review summarizes the success and limitations of bortezomib, and describes recent advances in the field, including, and most notably, the most recent FDA approval of carfilzomib in July, 2012, a second generation proteasome inhibitor. Other proteasome inhibitors currently in clin. trials and those that are currently exptl. grade will also be discussed.
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    18. 18
      Chen, D.; Frezza, M.; Schmitt, S.; Kanwar, J.; P. Dou, Q. Bortezomib as the First Proteasome Inhibitor Anticancer Drug: Current Status and Future Perspectives. Curr. Cancer Drug Targets 2011, 11 (3), 239– 253,  DOI: 10.2174/156800911794519752
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      18
      Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives
      Chen, D.; Frezza, M.; Schmitt, S.; Kanwar, J.; Dou, Q. P.
      Current Cancer Drug Targets (2011), 11 (3), 239-253CODEN: CCDTB9; ISSN:1568-0096. (Bentham Science Publishers Ltd.)
      A review. Targeting the ubiquitin-proteasome pathway has emerged as a rational approach in the treatment of human cancer. Based on pos. preclin. and clin. studies, bortezomib was subsequently approved for the clin. use as a front-line treatment for newly diagnosed multiple myeloma patients and for the treatment of relapsed/refractory multiple myeloma and mantle cell lymphoma, for which this drug has become the staple of treatment. The approval of bortezomib by the US Food and Drug Administration (FDA) represented a significant milestone as the first proteasome inhibitor to be implemented in the treatment of malignant disease. Bortezomib has shown a pos. clin. benefit either alone or as a part of combination therapy to induce chemo-/radio-sensitization or overcome drug resistance. One of the major mechanisms of bortezomib assocd. with its anticancer activity is through upregulation of NOXA, which is a proapoptotic protein, and NOXA may interact with the anti-apoptotic proteins of Bcl-2 subfamily Bcl-XL and Bcl-2, and result in apoptotic cell death in malignant cells. Another important mechanism of bortezomib is through suppression of the NF-κB signaling pathway resulting in the down-regulation of its anti-apoptotic target genes. Although the majority of success achieved with bortezomib has been in hematol. malignancies, its effect toward solid tumors has been less than encouraging. Addnl., the widespread clin. use of bortezomib continues to be hampered by the appearance of dose-limiting toxicities, drug-resistance and interference by some natural compds. These findings could help guide physicians in refining the clin. use of bortezomib, and encourage basic scientists to generate next generation proteasome inhibitors that broaden the spectrum of efficacy and produce a more durable clin. response in cancer patients. Other desirable applications for the use of proteasome inhibitors include the development of inhibitors against specific E3 ligases, which act at an early step in the ubiquitin-proteasome pathway, and the discovery of less toxic and novel proteasome inhibitors from natural products and traditional medicines, which may provide more viable drug candidates for cancer chemoprevention and the treatment of cancer patients in the future.
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    19. 19
      Pizzorno, L. Nothing Boring about Boron. Integr. Med. 2015, 14 (4), 35– 48
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      19
      Nothing Boring About Boron
      Pizzorno Lara
      Integrative medicine (Encinitas, Calif.) (2015), 14 (4), 35-48 ISSN:1546-993X.
      The trace mineral boron is a micronutrient with diverse and vitally important roles in metabolism that render it necessary for plant, animal, and human health, and as recent research suggests, possibly for the evolution of life on Earth. As the current article shows, boron has been proven to be an important trace mineral because it (1) is essential for the growth and maintenance of bone; (2) greatly improves wound healing; (3) beneficially impacts the body's use of estrogen, testosterone, and vitamin D; (4) boosts magnesium absorption; (5) reduces levels of inflammatory biomarkers, such as high-sensitivity C-reactive protein (hs-CRP) and tumor necrosis factor α (TNF-α); (6) raises levels of antioxidant enzymes, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase; (7) protects against pesticide-induced oxidative stress and heavy-metal toxicity; (8) improves the brains electrical activity, cognitive performance, and short-term memory for elders; (9) influences the formation and activity of key biomolecules, such as S-adenosyl methionine (SAM-e) and nicotinamide adenine dinucleotide (NAD(+)); (10) has demonstrated preventive and therapeutic effects in a number of cancers, such as prostate, cervical, and lung cancers, and multiple and non-Hodgkin's lymphoma; and (11) may help ameliorate the adverse effects of traditional chemotherapeutic agents. In none of the numerous studies conducted to date, however, do boron's beneficial effects appear at intakes > 3 mg/d. No estimated average requirements (EARs) or dietary reference intakes (DRIs) have been set for boron-only an upper intake level (UL) of 20 mg/d for individuals aged ≥ 18 y. The absence of studies showing harm in conjunction with the substantial number of articles showing benefits support the consideration of boron supplementation of 3 mg/d for any individual who is consuming a diet lacking in fruits and vegetables or who is at risk for or has osteopenia; osteoporosis; osteoarthritis (OA); or breast, prostate, or lung cancer.
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    20. 20
      Barranco, W. T.; Hudak, P. F.; Eckhert, C. D. Evaluation of Ecological and in Vitro Effects of Boron on Prostate Cancer Risk (United States). Cancer Causes Control 2007, 18, 71– 77,  DOI: 10.1007/s10552-006-0077-8
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      20
      Evaluation of ecological and in vitro effects of boron on prostate cancer risk (United States)
      Barranco Wade T; Hudak Paul F; Eckhert Curtis D
      Cancer causes & control : CCC (2007), 18 (1), 71-7 ISSN:0957-5243.
      OBJECTIVE: To determine: (1) the correlation of prostate cancer incidence and mortality with groundwater boron and selenium concentrations; and (2) the impact of boron on prostate cancer cell proliferation during co-treatment with alternative chemo-preventative agents, along with boron pre-treatment effects on cell sensitivity to ionizing radiation. METHODS: For regression analysis, data on prostate cancer incidence and mortality were obtained from the Texas Cancer Registry, while groundwater boron and selenium concentrations were derived from the Texas Water Development Board. Cultured DU-145 prostate cancer cells were used to assess the impact of boric acid on cell proliferation when applied in combination with selenomethionine and genistein, or preceding radiation exposure. RESULTS: Groundwater boron levels correlated with a decrease in prostate cancer incidence (R = 0.6) and mortality (R = 0.6) in state planning regions, whereas selenium did not (R = 0.1; R = 0.2). Growth inhibition was greater during combined treatments of boric acid and selenomethionine, or boric acid and genistein, versus singular treatments. 8-day boric acid pre-exposure enhanced the toxicity of ionizing radiation treatment, while dose-dependently decreasing the expression of anti-apoptotic protein Bcl-2. CONCLUSIONS: Increased groundwater boron concentrations, across the state of Texas, correlate with reduced risk of prostate cancer incidence and mortality. Also, boric acid improves the anti-proliferative effectiveness of chemo-preventative agents, selenomethionine and genistein, while enhancing ionizing radiation cell kill.
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    21. 21
      I. Scorei, R.; Popa, R. Boron-Containing Compounds as Preventive and Chemotherapeutic Agents for Cancer. Anti-Cancer Agents Med. Chem. 2010, 10 (4), 346– 351,  DOI: 10.2174/187152010791162289
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      There is no corresponding record for this reference.
    22. 22
      Baker, S. J.; Ding, C. Z.; Akama, T.; Zhang, Y. K.; Hernandez, V.; Xia, Y. Therapeutic Potential of Boron-Containing Compounds. Future Med. Chem. 2009, 1 (7), 1275– 1288,  DOI: 10.4155/fmc.09.71
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      22
      Therapeutic potential of boron-containing compounds
      Baker, Stephen J.; Ding, Charles Z.; Akama, Tsutomu; Zhang, Yong-Kang; Hernandez, Vincent; Xia, Yi
      Future Medicinal Chemistry (2009), 1 (7), 1275-1288CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)
      A review. Relative to C, H, N, and O2, very little is currently known about B in therapeutics. In addn., there are very few boron-contg. natural products identified to date to serve as leads for medicinal chemists. Perceived risks of using B and lack of synthetic methods to handle boron-contg. compds. have caused the medicinal chem. community to shy away from using the atom. However, phys., chem. and biol. properties of B offer medicinal chemists a rare opportunity to explore and pioneer new areas of drug discovery. B therapeutics are emerging that show different modes of inhibition against a variety of biol. targets. With one B-contg. therapeutic agent on the market and several more in various stages of clin. trials, the occurrence of this class of compd. is likely to grow over the next decade and B could become widely accepted as a useful element in future drug discovery.
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    23. 23
      Li, X.; Wang, X.; Zhang, J.; Hanagata, N.; Wang, X.; Weng, Q.; Ito, A.; Bando, Y.; Golberg, D. Hollow Boron Nitride Nanospheres as Boron Reservoir for Prostate Cancer Treatment. Nat. Commun. 2017, 8, 13936,  DOI: 10.1038/ncomms13936
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      23
      Hollow boron nitride nanospheres as boron reservoir for prostate cancer treatment
      Li, Xia; Wang, Xiupeng; Zhang, Jun; Hanagata, Nobutaka; Wang, Xuebin; Weng, Qunhong; Ito, Atsuo; Bando, Yoshio; Golberg, Dmitri
      Nature Communications (2017), 8 (), 13936CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)
      High global incidence of prostate cancer has led to a focus on prevention and treatment strategies to reduce the impact of this disease in public health. Boron compds. are increasingly recognized as preventative and chemotherapeutic agents. However, systemic administration of sol. boron compds. is hampered by their short half-life and low effectiveness. Here we report on hollow boron nitride (BN) spheres with controlled crystallinity and boron release that decrease cell viability and increase prostate cancer cell apoptosis. In vivo expts. on s.c. tumor mouse models treated with BN spheres demonstrated significant suppression of tumor growth. An orthotopic tumor growth model was also utilized and further confirmed the in vivo anti-cancer efficacy of BN spheres. Moreover, the administration of hollow BN spheres with paclitaxel leads to synergetic effects in the suppression of tumor growth. The work demonstrates that hollow BN spheres may function as a new agent for prostate cancer treatment.
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    24. 24
      Emanet Ciofani, M.; Şen, Ö.; Culha, M. Hexagonal Boron Nitride Nanoparticles for Prostate Cancer Treatment. ACS Appl. Nano Mater. 2020, 3 (3), 2364– 2372,  DOI: 10.1021/acsanm.9b02486
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      24
      Hexagonal Boron Nitride Nanoparticles for Prostate Cancer Treatment
      Emanet Ciofani, Melis; Sen, Ozlem; Culha, Mustafa
      ACS Applied Nano Materials (2020), 3 (3), 2364-2372CODEN: AANMF6; ISSN:2574-0970. (American Chemical Society)
      In recent years, hexagonal boron nitride (hBN) nanoparticles have gained significant interest in the medical and biomedical fields owing to their unique physicochem. properties including high surface area, low toxicity, and slow degrdn. in aq. media. With its possible degrdn. product boric acid (BA), a compd. of an essential element for the healthy function of biomachinery, a comparative evaluation of hBN and BA can reveal important information about the possible use of these novel materials in medicine. In this study, the influence of hBN and BA on prostate cancer cells was comparatively investigated by emphasizing the effect mechanisms through a no. of mol. tests. First, the high cellular internalization capacity of hBN, as well as the high cellular sensitivity of prostate cancer cells that cause a significant cell viability decrease on the contrary of healthy cells, was evaluated. In order to evaluate their cancer repression effect, mitochondrial dysfunction, reactive oxygen species (ROS) prodn., and cell death mechanisms were investigated. Finally, the metastatic capacities of the cancer cells were tested by monitoring the cytoskeleton structures and migration capacity of cells exposed to hBN. The results clearly indicate that hBN promotes prostate cancer cell apoptosis by seriously increasing ROS prodn. Moreover, their metastatic capacity decrement encouraged us to exploit hBN as a safe therapeutic agent against prostate cancer.
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    25. 25
      Gallardo-Williams, M. T.; Chapin, R. E.; King, P. E.; Moser, G. J.; Goldsworthy, T. L.; Morrison, J. P.; Maronpot, R. R. Boron Supplementation Inhibits the Growth and Local Expression of IGF-1 in Human Prostate Adenocarcinoma (LNCaP) Tumors in Nude Mice. Toxicol. Pathol. 2004, 32 (1), 73– 78,  DOI: 10.1080/01926230490260899
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      25
      Boron Supplementation Inhibits the Growth and Local Expression of IGF-1 in Human Prostate Adenocarcinoma (LNCaP) Tumors in Nude Mice
      Gallardo-Williams, Maria T.; Chapin, Robert E.; King, Paula E.; Moser, Glenda J.; Goldsworthy, Thomas L.; Morrison, James P.; Maronpot, Robert R.
      Toxicologic Pathology (2004), 32 (1), 73-78CODEN: TOPADD; ISSN:0192-6233. (Taylor & Francis, Inc.)
      Prostate-specific antigen (PSA) is a serine protease and one of the most abundant proteins secreted by the human prostate epithelium. PSA is used as a well-established marker of prostate cancer. The involvement of PSA in several early events leading to the development of malignant prostate tumors has made it a target for prevention and intervention. It is thought that PSA cleaves insulin-like growth factor binding protein-3 (IGFBP-3), providing increased local levels of IGF-1, leading to tumor growth. Sep., there are data that suggest an enzymic regulatory role for dietary boron, which is a serine protease inhibitor. In this study we have addressed the use of boric acid as a PSA inhibitor in an animal study. We have previously reported that low concns. (6 ug/mL) of boric acid can partially inhibit the proteolytic activity of purified PSA towards a synthetic fluorogenic substrate. Also, by Western blot we have followed the degrdn. of fibronectin by enzymically active PSA and have found significant inhibition in the presence of boric acid. We proposed that dietary supplementation with boric acid would inhibit PSA and reduce the development and proliferation of prostate carcinomas in an animal model. We tested this hypothesis using nude mice implanted s.c. with LNCaP cells in Matrigel. Two groups (10 animals/group) were dosed with boric acid solns. (1.7, 9.0 mgB/kg/day) by gavage. Control group received only water. Tumor sizes were measured weekly for 8 wk. Serum PSA and IGF-1 levels were detd. at terminal sacrifice. The size of tumors was decreased in mice exposed to the low and high dose of boric acid by 38% and 25%, resp. Serum PSA levels decreased by 88.6% and 86.4%, resp., as compared to the control group. There were morphol. differences between the tumors in control and boron-dosed animals, including a significantly lower incidence of mitotic figures in the boron-supplemented groups. Circulating IGF-1 levels were not different among groups, though expression of IGF-1 in the tumors was markedly reduced by boron treatment, which we have shown by immunohistochem. These data indicate that low-level dietary boron supplementation reduced tumor size and content of a tumor trophic factor, IGF-1. This promising model is being evaluated in further studies.
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    26. 26
      Cohen, P.; Peehl, D. M.; Graves, H. C. B.; Rosenfeld, R. G. Biological Effects of Prostate Specific Antigen as an Insulin-like Growth Factor Binding Protein-3 Protease. J. Endocrinol. 1994, 142 (3), 407– 415,  DOI: 10.1677/joe.0.1420407
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      26
      Biological effects of prostate specific antigen as an insulin-like growth factor binding protein-3 protease
      Cohen, P.; Peehl, D. M.; Graves, H. C. B.; Rosenfield, R. G.
      Journal of Endocrinology (1994), 142 (3), 407-15CODEN: JOENAK; ISSN:0022-0795.
      Prostate specific antigen (PSA) is an insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) protease found in seminal plasma and produced by prostatic epithelial cells (PC-E) in vivo. The authors examd. the effects of PSA-proteolysis of IGFBP-3 on the affinity of IGFBP-3 fragments for IGFs and on the mitogenic action of IGFs on PCE-E. Recombinant human IGFBP-3 was cleaved by PSA, then incubated with 125I-IGF-I or -II in the presence of varying concns. of unlabeled peptides, and then crosslinking electrophoresis and densitometric anal. were performed. While the affinity of IGF-II for the PSA-generated IGFBP-3 fragments fell slightly compared to intact IGFBP-3, the affinity of the PSA-generated IGFBP-3 fragments for IGF-I fell by ten fold. The addn. of IGF-I or -II to PC-E in serum-free culture conditions resulted in a two-fold stimulation of cell no. compared to control. The presence of IGFBP-3 in the media blocked the IGF-induced stimulation, but had no independent effect in the absence of IGFs. When PSA was added to PC-E cultures to which both IGF-I or -II and IGFBP-3 were added, the inhibitory effects of IGFBP-3 on IGF mitogenesis were reversed. Apparently, PSA decreases the affinity of IGFBP-3 for IGF and can potentiate IGF action in the presence of inhibitory IGFBP-3. This phenomenon may contribute to normal and malignant prostate growth.
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    27. 27
      Tian, Y.; Guo, Z.; Zhang, T.; Lin, H.; Li, Z.; Chen, J.; Deng, S.; Liu, F. Inorganic Boron-Based Nanostructures: Synthesis, Optoelectronic Properties, and Prospective Applications. Nanomaterials 2019, 9 (4), 538,  DOI: 10.3390/nano9040538
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      Inorganic boron-based nanostructures: synthesis, optoelectronic properties, and prospective applications
      Tian, Yan; Guo, Zekun; Zhang, Tong; Lin, Haojian; Li, Zijuan; Chen, Jun; Deng, Shaozhi; Liu, Fei
      Nanomaterials (2019), 9 (4), 538CODEN: NANOKO; ISSN:2079-4991. (MDPI AG)
      A review. Inorg. boron-based nanostructures have great potential for field emission (FE), flexible displays, superconductors, and energy storage because of their high m.p., low d., extreme hardness, and good chem. stability. Until now, most researchers have been focused on one-dimensional (1D) boron-based nanostructures (rare earth boride (REB6) nanowires, boron nanowires, and nanotubes). Currently, two-dimensional (2D) borophene attracts most of the attention, due to its unique phys. and chem. properties, which make it quite different from its corresponding bulk counterpart. Here, we offer a comprehensive review on the synthesis methods and optoelectronics properties of inorg. boron-based nanostructures, which are mainly concd. on 1D rare earth boride nanowires, boron monoelement nanowires, and nanotubes, as well as 2D borophene and borophane. In Section I, the synthesis methods of inorg. boron-based nanostructures are systematically introduced. In Section II, we classify their optical and elec. transport properties (field emission, optical absorption, and photoconductive properties). In the last section, we evaluate the optoelectronic behaviors of the known inorg. boron-based nanostructures and propose their future applications.
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      Mateti, S.; Wong, C. S.; Liu, Z.; Yang, W.; Li, Y.; Li, L. H.; Chen, Y. Biocompatibility of Boron Nitride Nanosheets. Nano Res. 2018, 11 (1), 334– 342,  DOI: 10.1007/s12274-017-1635-y
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      Biocompatibility of boron nitride nanosheets
      Mateti, Srikanth; Wong, Cynthia S.; Liu, Zhen; Yang, Wenrong; Li, Yuncang; Li, Lu Hua; Chen, Ying
      Nano Research (2018), 11 (1), 334-342CODEN: NRAEB5; ISSN:1998-0000. (Springer GmbH)
      The properties and applications of boron nitride (BN) nanosheets are complementary to those of graphene, with advantages in chem. and thermal stability. Biocompatibility is an important property for future biomedical applications but has not been investigated exptl. We studied the biocompatibility of BN nanosheets of different sizes and compared it with that of BN nanoparticles in osteoblast-like cells (SaOS2). Our results showed that the biocompatibility of BN nanomaterials depends on their size, shape, structure, and surface chem. properties. ESR measurement revealed that unsatd. B atoms located at the nanosheet edges or on the particle surface are responsible for the cell death.
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    29. 29
      Orme, M. E.; Chaplain, M. A. J. Two-Dimensional Models of Tumour Angiogenesis and Anti-Angiogenesis Strategies. IMA J. Math. Appl. Med. Biol. 1997, 14 (3), 189– 205,  DOI: 10.1093/imammb/14.3.189
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      Two-dimensional models of tumour angiogenesis and anti-angiogenesis strategies
      Orme M E; Chaplain M A
      IMA journal of mathematics applied in medicine and biology (1997), 14 (3), 189-205 ISSN:0265-0746.
      There is a very strong link between the vascularization of a tumour and the spread of the disease, both locally and to distant sites (Gimbrone et al., 1974, J. Natl. Cancer Inst. 52, 413-27; Muthukkaruppan et al., 1982, J. Natl. Cancer Inst. 69, 699-704; Ellis & Fiddler, 1995, Lancet 346, 388-9). A tumour becomes vascularized by a process known as angiogenesis. Tumour angiogenesis is initiated by the release of diffusible substances by the tumour, whereby neighbouring capillary vessels are stimulated to grow and eventually penetrate the tumour. Anti-angiogenesis has been proposed as a potential strategy for the treatment of cancer (Folkman, 1995, Nature Med. 1, 21-31; Harris et al., 1996, Breast Cancer Res. Treat. 38, 97-108). In this paper, a mathematical model of the development of the tumour vasculature is presented. By suitable manipulation of the model parameters, we simulate various anti-angiogenesis strategies and we examine the roles that haptotaxis and chemotaxis may play during the growth of the neovasculature. The model is simulated in two space dimensions (on a square domain) so that it is, in theory, experimentally reproducible and any predictions of the model can therefore be tested.
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    30. 30
      Hillen, F.; Griffioen, A. W. Tumour Vascularization: Sprouting Angiogenesis and Beyond. Cancer Metastasis Rev. 2007, 26 (3–4), 489– 502,  DOI: 10.1007/s10555-007-9094-7
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      30
      Tumour vascularization: sprouting angiogenesis and beyond
      Hillen Femke; Griffioen Arjan W
      Cancer metastasis reviews (2007), 26 (3-4), 489-502 ISSN:0167-7659.
      Tumour angiogenesis is a fast growing domain in tumour biology. Many growth factors and mechanisms have been unravelled. For almost 30 years, the sprouting of new vessels out of existing ones was considered as an exclusive way of tumour vascularisation. However, over the last years several additional mechanisms have been identified. With the discovery of the contribution of intussusceptive angiogenesis, recruitment of endothelial progenitor cells, vessel co-option, vasculogenic mimicry and lymphangiogenesis to tumour growth, anti-tumour targeting strategies will be more complex than initially thought. This review highlights these processes and intervention as a potential application in cancer therapy. It is concluded that future anti-vascular therapies might be most beneficial when based on multimodal anti-angiogenic, anti-vasculogenic mimicry and anti-lymphangiogenic strategies.
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      Nishida, N.; Yano, H.; Nishida, T.; Kamura, T.; Kojiro, M. Angiogenesis in Cancer. Vasc. Health Risk Manag. 2006, 2 (3), 213– 219,  DOI: 10.2147/vhrm.2006.2.3.213
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      Angiogenesis in cancer
      Nishida, Naoyo; Yano, Hirohisa; Nishida, Takashi; Kamura, Toshiharu; Kojiro, Masamichi
      Vascular Health and Risk Management (2006), 2 (3), 213-219CODEN: VHRMAT; ISSN:1176-6344. (Dove Medical Press (NZ) Ltd.)
      A review. New growth in the vascular network is important since the proliferation, as well as metastatic spread, of cancer cells depends on an adequate supply of oxygen and nutrients and the removal of waste products. New blood and lymphatic vessels form through processes called angiogenesis and lymphangiogenesis, resp. Angiogenesis is regulated by both activator and inhibitor mols. More than a dozen different proteins have been identified as angiogenic activators and inhibitors. Levels of expression of angiogenic factors reflect the aggressiveness of tumor cells. The discovery of angiogenic inhibitors should help to reduce both morbidity and mortality from carcinomas. Thousands of patients have received antiangiogenic therapy to date. Despite their theor. efficacy, antiangiogenic treatments have not proved beneficial in terms of long-term survival. There is an urgent need for a new comprehensive treatment strategy combining antiangiogenic agents with conventional cytoreductive treatments in the control of cancer.
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      Abunahla, H.; Mohammad, B.; Alazzam, A.; Jaoude, M. A.; Al-Qutayri, M.; Abdul Hadi, S.; Al-Sarawi, S. F. MOMSense: Metal-Oxide-Metal Elementary Glucose Sensor. Sci. Rep. 2019, 9 (1), 5524,  DOI: 10.1038/s41598-019-41892-w
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      MOMSense: Metal-Oxide-Metal Elementary Glucose Sensor
      Abunahla Heba; Mohammad Baker; Al-Qutayri Mahmoud; Abdul Hadi Sabina; Alazzam Anas; Jaoude Maguy Abi; Al-Sarawi Said F
      Scientific reports (2019), 9 (1), 5524 ISSN:.
      In this paper, we present a novel Pt/CuO/Pt metal-oxide-metal (MOM) glucose sensor. The devices are fabricated using a simple, low-cost standard photolithography process. The unique planar structure of the device provides a large electrochemically active surface area, which acts as a nonenzymatic reservoir for glucose oxidation. The sensor has a linear sensing range between 2.2 mM and 10 mM of glucose concentration, which covers the blood glucose levels for an adult human. The distinguishing property of this sensor is its ability to measure glucose at neutral pH conditions (i.e. pH = 7). Furthermore, the dilution step commonly needed for CuO-based nonenzymatic electrochemical sensors to achieve an alkaline medium, which is essential to perform redox reactions in the absence of glucose oxidase, is eliminated, resulting in a lower-cost and more compact device.
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      Kerbel, R. S.; Kamen, B. A. The Anti-Angiogenic Basis of Metronomic Chemotherapy. Nat. Rev. Cancer 2004, 4 (6), 423– 436,  DOI: 10.1038/nrc1369
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      The anti-angiogenic basis of metronomic chemotherapy
      Kerbel, Robert S.; Kamen, Barton A.
      Nature Reviews Cancer (2004), 4 (6), 423-436CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)
      A review. In addn. to proliferating cancer cells and various types of normal cells, such as those of the bone marrow, conventional cytotoxic chemotherapeutics affect the endothelium of the growing tumor vasculature. The anti-angiogenic efficacy of chemotherapy seems to be optimized by administering comparatively low doses of drug on a frequent or continuous schedule, with no extended interruptions - sometimes referred to as 'metronomic' chemotherapy. In addn. to reduced acute toxicity, the efficacy of metronomic chemotherapy seems to increase when administered in combination with specific anti-angiogenic drugs. Gaining better insight into the mechanisms of these effects could lessen or even eliminate the empiricism used to det. the optimal dose and schedule for metronomic chemotherapy regimens.
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      Yoncheva, K.; Momekov, G. Antiangiogenic Anticancer Strategy Based on Nanoparticulate Systems. Expert Opin. Drug Delivery 2011, 8 (8), 1041– 1056,  DOI: 10.1517/17425247.2011.585155
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      Antiangiogenic anticancer strategy based on nanoparticulate systems
      Yoncheva, Krassimira; Momekov, Georgi
      Expert Opinion on Drug Delivery (2011), 8 (8), 1041-1056CODEN: EODDAW; ISSN:1742-5247. (Informa Healthcare)
      A review. Introduction: Angiogenesis is a process that provides a blood supply for cancer cells. The discovery that the blockade of this blood supply results in the inhibition of cancer cell growth has been applied in cancer treatment. This antiangiogenic strategy is mainly directed at the inhibition of the binding process between proangiogenic growth factors and their receptors or the inhibition of the activity of proteolytic enzymes of the extracellular matrix. The toxicity of some antiangiogenic agents, such as small-mol. inhibitors, and the instability of antiangiogenic proteins require their formulation in an appropriate delivery system. On the other hand, active drug targeting to selective markers expressed on tumor vasculature could improve antiangiogenic treatment.Areas covered: The present review focuses on nanoparticulate systems (nanoparticles, liposomes, polymeric micelles, etc.) because their properties could enable both the targeting of endothelial cells and the efficient delivery of antiangiogenic agents. The most important properties of nanoparticles that influence both processes, such as their size, charge and surface modification, are also discussed. Various examples illustrating the targeting ability of nanoparticles are reported, in particular conjugated nanoparticles targeting VEGF and its receptors, fibroblast growth factor and its receptors, EGFRs, MMPs, tubulin function and so on.Expert opinion: Targeting of nanoparticles (e.g., by tumor-penetrating peptides) allows the co-administration of antiangiogenic and anticancer drugs, facilitates drug penetration into extravascular tumor tissue and improves the therapeutic effect at reduced drug doses.
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      Ma, J.; Pulfer, S.; Li, S.; Chu, J.; Reed, K.; Gallo, J. M. Pharmacodynamic-Mediated Reduction of Temozolomide Tumor Concentrations by the Angiogenesis Inhibitor TNP-470. Cancer Res. 2001, 61 (14), 5491– 5498
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      Pharmacodynamic-mediated reduction of temozolomide tumor concentrations by the angiogenesis inhibitor TNP-470
      Ma, Jianguo; Pulfer, Sharon; Li, Shaolan; Chu, Jianxiong; Reed, Karin; Gallo, James M.
      Cancer Research (2001), 61 (14), 5491-5498CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)
      This work evaluated a potential drug interaction between the angiogenesis inhibitor O-(N-chloroacetylcarbamoyl)furnagillol (TNP-470) and the alkylating agent temozolomide (TMZ) in xenograft models that differentially expressed vascular endothelial growth factor (VEGF), a driving force for angiogenesis. Nude rats bearing either s.c. low-VEGF (V-) or high-VEGF (V+) or intracerebral V+ gliomas were administered either a multiple-dose regimen of TNP-470 or vehicle control. One day after the last dose of vehicle or TNP-470, a steady-state dosage regimen of TMZ was administered with subsequent collection and HPLC anal. of plasma and either tumor homogenate or tumor microdialysis steady-state TMZ concns., and in some cases [5-(3-methyltriazen-1-yl)imidazole-4-carboximide] MTIC, its active metabolite. Microvessel d. (MVD) was quantitated by image anal. with an anti-CD31 method. Statistical analyses of pharmacokinetic and pharmacodynamic end points in the control and TNP-470-treated groups were completed by nonparametric tests. In both the s.c. and intracerebral V+ models, TNP-470 treatment reduced tumor TMZ concns. and tumor:plasma concn. ratios compared with controls, being reduced an av. of 25% and 50% in the s.c. and intracerebral tumors, resp. MTIC concns. in V+ s.c. tumors also were reduced by 50% in the presence of TNP-470. Consistent with the lower extent of neovascularization in the V- tumors, tumor TMZ and MTIC concns. were not different in s.c. tumors between the TNP-470-treated and control groups. MVD was reduced by TNP-470 compared with controls in the V+ tumors, but was unaltered in V- tumors, attesting to the use of MVD as a pharmacodynamic end point and the effectiveness of TNP-470 as an angiogenesis inhibitor. Angiogenesis inhibitors' pharmacodynamic actions on tumor angiogenesis can reduce tumor concns. of coadministered anticancer agents.
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      Desai, N. Challenges in Development of Nanoparticle-Based Therapeutics. AAPS J. 2012, 14 (2), 282– 295,  DOI: 10.1208/s12248-012-9339-4
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      Challenges in Development of Nanoparticle-Based Therapeutics
      Desai, Neil
      AAPS Journal (2012), 14 (2), 282-295CODEN: AJAOB6; ISSN:1550-7416. (Springer)
      A review. In recent years, nanotechnol. has been increasingly applied to the area of drug development. Nanoparticle-based therapeutics can confer the ability to overcome biol. barriers, effectively deliver hydrophobic drugs and biologics, and preferentially target sites of disease. However, despite these potential advantages, only a relatively small no. of nanoparticle-based medicines have been approved for clin. use, with numerous challenges and hurdles at different stages of development. The complexity of nanoparticles as multi-component three dimensional constructs requires careful design and engineering, detailed orthogonal anal. methods, and reproducible scale-up and manufg. process to achieve a consistent product with the intended physicochem. characteristics, biol. behaviors, and pharmacol. profiles. The safety and efficacy of nanomedicines can be influenced by minor variations in multiple parameters and need to be carefully examd. in preclin. and clin. studies, particularly in context of the biodistribution, targeting to intended sites, and potential immune toxicities. Overall, nanomedicines may present addnl. development and regulatory considerations compared with conventional medicines, and while there is generally a lack of regulatory stds. in the examn. of nanoparticle-based medicines as a unique category of therapeutic agents, efforts are being made in this direction. This review summarizes challenges likely to be encountered during the development and approval of nanoparticle-based therapeutics, and discusses potential strategies for drug developers and regulatory agencies to accelerate the growth of this important field.
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      Mukherjee, S.; Patra, C. R. Therapeutic Application of Anti-Angiogenic Nanomaterials in Cancers. Nanoscale 2016, 8 (25), 12444– 12470,  DOI: 10.1039/C5NR07887C
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      Therapeutic application of anti-angiogenic nanomaterials in cancers
      Mukherjee, Sudip; Patra, Chitta Ranjan
      Nanoscale (2016), 8 (25), 12444-12470CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
      Angiogenesis, the formation of new blood vessels from pre-existing vasculature, plays a vital role in physiol. and pathol. processes (embryonic development, wound healing, tumor growth and metastasis). The overall balance of angiogenesis inside the human body is maintained by pro- and anti-angiogenic signals. The processes by which drugs inhibit angiogenesis as well as tumor growth are called the anti-angiogenesis technique, a most promising cancer treatment strategy. Over the last couple of decades, scientists have been developing angiogenesis inhibitors for the treatment of cancers. However, conventional anti-angiogenic therapy has several limitations including drug resistance that can create problems for a successful therapeutic strategy. Therefore, a new comprehensive treatment strategy using antiangiogenic agents for the treatment of cancer is urgently needed. Recently researchers have been developing and designing several nanoparticles that show anti-angiogenic properties. These nanomedicines could be useful as an alternative strategy for the treatment of various cancers using anti-angiogenic therapy. In this review article, we critically focus on the potential application of anti-angiogenic nanomaterial and nanoparticle based drug/siRNA/peptide delivery systems in cancer therapeutics. We also discuss the basic and clin. perspectives of anti-angiogenesis therapy, highlighting its importance in tumor angiogenesis, current status and future prospects and challenges.
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      Zhang, C.; Ni, D.; Liu, Y.; Yao, H.; Bu, W.; Shi, J. Magnesium Silicide Nanoparticles as a Deoxygenation Agent for Cancer Starvation Therapy. Nat. Nanotechnol. 2017, 12 (4), 378– 386,  DOI: 10.1038/nnano.2016.280
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      Magnesium silicide nanoparticles as a deoxygenation agent for cancer starvation therapy
      Zhang, Chen; Ni, Dalong; Liu, Yanyan; Yao, Heliang; Bu, Wenbo; Shi, Jianlin
      Nature Nanotechnology (2017), 12 (4), 378-386CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)
      A material that rapidly absorbs mol. oxygen (known as an oxygen scavenger or deoxygenation agent (DOA)) has various industrial applications, such as in food preservation, anticorrosion of metal and coal deoxidn. Given that oxygen is vital to cancer growth, to starve tumors through the consumption of intratumoral oxygen is a potentially useful strategy in fighting cancer. Here we show that an injectable polymer-modified magnesium silicide (Mg2Si) nanoparticle can act as a DOA by scavenging oxygen in tumors and form byproducts that block tumor capillaries from being reoxygenated. The nanoparticles are prepd. by a self-propagating high-temp. synthesis strategy. In the acidic tumor microenvironment, the Mg2Si releases silane, which efficiently reacts with both tissue-dissolved and Hb-bound oxygen to form silicon oxide (SiO2) aggregates. This in situ formation of SiO2 blocks the tumor blood capillaries and prevents tumors from receiving new supplies of oxygen and nutrients.
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    39. 39
      Ranji-Burachaloo, H.; Karimi, F.; Xie, K.; Fu, Q.; Gurr, P. A.; Dunstan, D. E.; Qiao, G. G. MOF-Mediated Destruction of Cancer Using the Cell’s Own Hydrogen Peroxide. ACS Appl. Mater. Interfaces 2017, 9 (39), 33599– 33608,  DOI: 10.1021/acsami.7b07981
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      MOF-Mediated Destruction of Cancer Using the Cell's Own Hydrogen Peroxide
      Ranji-Burachaloo, Hadi; Karimi, Fatemeh; Xie, Ke; Fu, Qiang; Gurr, Paul A.; Dunstan, Dave E.; Qiao, Greg G.
      ACS Applied Materials & Interfaces (2017), 9 (39), 33599-33608CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
      A novel reduced iron metal-org. framework nanoparticle with cytotoxicity specific to cancer cells is presented. This nanoparticle was prepd. via a hydrothermal method, reduced using hydroquinone, and finally conjugated with folic acid (namely, rMOF-FA). The synthesized nanoparticle shows the controlled release of iron in an acidic ex-vivo environment. Iron present on the rMOF-FA and released into soln. can react with high levels of hydrogen peroxide found specifically in cancer cells to increase the hydroxyl radical concn. The hydroxyl radicals oxidize proteins, lipids, and/or DNA within the biol. system to decrease cell viability. In vitro expts. demonstrate that this novel nanoparticle is cytotoxic to cancer cells (HeLa) through generation of OH• inside the cells. At low concns. of rMOF-FA, the cancer cell viability decreases dramatically, with no obvious redn. of normal cell (NIH-3T3) viability. The calcd. half-max. inhibitory concn. value (IC50) was 43 μg/mL for HeLa cells, which was significantly higher than 105 μg/mL for NIH-3T3. This work thus demonstrates a new type of agent for controlled hydroxyl radical generation using the Fenton reaction to kill the tumor cells.
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      Qian, X.; Zhang, J.; Gu, Z.; Chen, Y. Nanocatalysts-Augmented Fenton Chemical Reaction for Nanocatalytic Tumor Therapy. Biomaterials 2019, 211, 1– 13,  DOI: 10.1016/j.biomaterials.2019.04.023
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      Nanocatalysts-augmented Fenton chemical reaction for nanocatalytic tumor therapy
      Qian, Xiaoqin; Zhang, Jun; Gu, Zi; Chen, Yu
      Biomaterials (2019), 211 (), 1-13CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
      A review. It is the challenging goal in cancer biomedicine to search novel cancer-therapeutic modality with concurrent high therapeutic efficiency on combating cancer and low side effects to normal cells/tissues. The recently developed nanocatalytic cancer therapy based on catalytic Fenton reaction represents one of the promising paradigms for potential clin. translation, which has got fast progress very recently. This progress report discusses the rational design and fabrication of Fenton reaction-based nanocatalysts for triggering the in-situ Fenton chem. reaction within tumor microenvironment to generate highly toxic hydroxyl radicals (•OH), which is highly efficient for killing the cancer cells and suppressing the tumor growth. Several strategies for optimizing the nanocatalytic cancer-therapeutic efficiency of Fenton reaction have been highlighted, including screening high-performance Fenton nanocatalysts, increasing peroxide-hydrogen amts. as the reactants, changing the Fenton-reaction conditions (e.g., temp., acidity and photo-triggering), and Fenton reaction-based synergistic cancer therapy such as some sequential nanocatalytic reactions with improved therapeutic outcome. The facing challenges and future developments of Fenton reaction-based nanocatalytic cancer therapy are also discussed for further promoting the clin. translation of this emerging cancer-therapeutic modality to benefit the cancer patients.
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      Halliwell, B.; Clement, M. V.; Long, L. H. Hydrogen Peroxide in the Human Body. FEBS Lett. 2000, 486 (1), 10– 13,  DOI: 10.1016/S0014-5793(00)02197-9
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      Hydrogen peroxide in the human body
      Halliwell, B.; Clement, M. V.; Long, L. H.
      FEBS Letters (2000), 486 (1), 10-13CODEN: FEBLAL; ISSN:0014-5793. (Elsevier Science B.V.)
      A review with 89 refs. Hydrogen peroxide (H2O2) is widely regarded as a cytotoxic agent whose levels must be minimized by the action of antioxidant defense enzymes. In fact, H2O2 is poorly reactive in the absence of transition metal ions. Exposure of certain human tissues to H2O2 may be greater than is commonly supposed: substantial amts. of H2O2 can be present in beverages commonly drunk (esp. instant coffee), in freshly voided human urine, and in exhaled air. Levels of H2O2 in the human body may be controlled not only by catabolism but also by excretion, and H2O2 could play a role in the regulation of renal function and as an antibacterial agent in the urine. Urinary H2O2 levels are influenced by diet, but under certain conditions might be a valuable biomarker of 'oxidative stress'.
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    42. 42
      Szatrowski, T. P.; Nathan, C. F. Production of Large Amounts of Hydrogen Peroxide by Human Tumor Cells. Cancer Res. 1991, 51 (3), 794– 798
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      Production of large amounts of hydrogen peroxide by human tumor cells
      Szatrowski, Ted P.; Nathan, Carl F.
      Cancer Research (1991), 51 (3), 794-8CODEN: CNREA8; ISSN:0008-5472.
      Few nonphagocytic cells are known to generate reactive oxygen intermediates. Based on horseradish peroxidase-dependent, catalase-inhibitable oxidn. of fluorescent scopoletin, seven human tumor cell lines constitutively elaborated H2O2 at rates (up to 0.5 nmol/104) cells/h) large enough that cumulative amts. at 4 h were comparable to the amt. of H2O2 produced by phorbol ester-triggered neutrophils. Superoxide dismutase-inhibitable ferricytochrome c redn. was detectable at much lower rates. H2O2 prodn. was inhibited by diphenyleneiodonium, a flavoprotein binder (concn. producing 50% inhibition, 0.3 μM), and diethyldithiocarbamate, a divalent cation chelator (concn. producing 50% inhibition, 3 μM), but not by cyanide or azide, inhibitors of electron transport, or by agents that inhibit xanthine oxidase, polyamine oxidase, or cytochrome P 450. Cytochrome b559, present in human phagocytes and lymphocytes, was undetectable in these tumor cells by a sensitive spectrophotometric method. Mouse fibroblasts transfected with human tyrosinase cDNA made melanin, but not H2O2. Constitutive generation of large amts. of reactive oxygen intermediates, if it occurs in vivo, might contribute to the ability of some tumors to mutate, inhibit antiproteases, injure local tissues, and therefore promote tumor heterogeneity, invasion, and metastasis.
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    43. 43
      Kim, J.; Cho, H. R.; Jeon, H.; Kim, D.; Song, C.; Lee, N.; Choi, S. H.; Hyeon, T. Continuous O2-Evolving MnFe2O4 Nanoparticle-Anchored Mesoporous Silica Nanoparticles for Efficient Photodynamic Therapy in Hypoxic Cancer. J. Am. Chem. Soc. 2017, 139 (32), 10992– 10995,  DOI: 10.1021/jacs.7b05559
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      43
      Continuous O2-Evolving MnFe2O4 Nanoparticle-Anchored Mesoporous Silica Nanoparticles for Efficient Photodynamic Therapy in Hypoxic Cancer
      Kim, Jonghoon; Cho, Hye Rim; Jeon, Hyejin; Kim, Dokyoon; Song, Changyeong; Lee, Nohyun; Choi, Seung Hong; Hyeon, Taeghwan
      Journal of the American Chemical Society (2017), 139 (32), 10992-10995CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Therapeutic effects of photodynamic therapy (PDT) are limited by cancer hypoxia because the PDT process is dependent on O2 concn. Herein, we design biocompatible manganese ferrite nanoparticle-anchored mesoporous silica nanoparticles (MFMSNs) to overcome hypoxia, consequently enhancing the therapeutic efficiency of PDT. By exploiting the continuous O2-evolving property of MnFe2O4 nanoparticles through the Fenton reaction, MFMSNs relieve hypoxic condition using a small amt. of nanoparticles and improve therapeutic outcomes of PDT for tumors in vivo. In addn., MFMSNs exhibit T2 contrast effect in magnetic resonance imaging (MRI), allowing in vivo tracking of MFMSNs. These findings demonstrate great potential of MFMSNs for theranostic agents in cancer therapy.
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    44. 44
      Peng, Y.; Wang, Z.; Liu, W.; Zhang, H.; Zuo, W.; Tang, H.; Chen, F.; Wang, B. Size- and Shape-Dependent Peroxidase-like Catalytic Activity of MnFe2O4 Nanoparticles and Their Applications in Highly Efficient Colorimetric Detection of Target Cancer Cells. Dalt. Trans. 2015, 44 (28), 12871– 12877,  DOI: 10.1039/C5DT01585E
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      Size- and shape-dependent peroxidase-like catalytic activity of MnFe2O4 Nanoparticles and their applications in highly efficient colorimetric detection of target cancer cells
      Peng, Yunhua; Wang, Zhiyi; Liu, Weisheng; Zhang, Haoli; Zuo, Wei; Tang, Huiang; Chen, Fengjuan; Wang, Baodui
      Dalton Transactions (2015), 44 (28), 12871-12877CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
      The catalytic activity of nanocrystal catalysts depends strongly on their chem. compn., size, and shape. Herein, the authors report four different sizes and shapes of MnFe2O4 nanoparticles (NPs) prepd. by a hydrothermal procedure. In addn., the size- and shape-dependent peroxidase-like activity of these NPs was first explored using 3,3',5,5'-tetramethyl-benzidine and H2O2 as peroxidase substrates. The peroxidase-like activities of the MnFe2O4 NPs were size- and shape-dependent and followed the order of 4 nm (spherical) > 18 nm (plate-like) > 27 nm (near-cubic) > 16 nm (spherical); this order was closely related to their surface-to-vol. ratio and atom arrangements. Such a study is of great significance for peroxidase nanomimetics with enhanced activity and use. Furthermore, folic acid (FA)-conjugated MnFe2O4 NPs allow the detection of folate receptor-rich cancer cells. Such study can be widely used for the identification of important target mols.
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      Fu, J.; Shao, Y.; Wang, L.; Zhu, Y. Lysosome-Controlled Efficient ROS Overproduction against Cancer Cells with a High PH-Responsive Catalytic Nanosystem. Nanoscale 2015, 7 (16), 7275– 7283,  DOI: 10.1039/C5NR00706B
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      Lysosome-controlled efficient ROS overproduction against cancer cells with a high pH-responsive catalytic nanosystem
      Fu, Jingke; Shao, Yiran; Wang, Liyao; Zhu, Yingchun
      Nanoscale (2015), 7 (16), 7275-7283CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
      Excess reactive oxygen species (ROS) have been proved to damage cancer cells efficiently. ROS overprodn. is thus greatly desirable for cancer therapy. To date, ROS prodn. is generally uncontrollable and outside cells, which always bring severe side-effects in the vasculature. Since most ROS share a very short half-life and primarily react close to their site of formation, it would be more efficient if excess ROS are controllably produced inside cancer cells. Herein, we report an efficient lysosome-controlled ROS overprodn. via a pH-responsive catalytic nanosystem (FeOx-MSNs), which catalyze the decompn. of H2O2 to produce considerable ROS selectively inside the acidic lysosomes (pH 5.0) of cancer cells. After a further incorporation of ROS-sensitive TMB into the nanosystem (FeOx-MSNs-TMB), both a distinct cell labeling and an efficient death of breast carcinoma cells are obtained. This lysosome-controlled efficient ROS overprodn. suggests promising applications in cancer treatments.
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      He, W.; Zhou, Y. T.; Wamer, W. G.; Boudreau, M. D.; Yin, J. J. Mechanisms of the PH Dependent Generation of Hydroxyl Radicals and Oxygen Induced by Ag Nanoparticles. Biomaterials 2012, 33 (30), 7547– 7555,  DOI: 10.1016/j.biomaterials.2012.06.076
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      Mechanisms of the pH dependent generation of hydroxyl radicals and oxygen induced by Ag nanoparticles
      He, Weiwei; Zhou, Yu-Ting; Wamer, Wayne G.; Boudreau, Mary D.; Yin, Jun-Jie
      Biomaterials (2012), 33 (30), 7547-7555CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
      Many of the chem. and biol. effects of silver nanoparticles (Ag NPs) are attributed to the generation of reactive oxygen species (ROS). ESR spectroscopy was used to provide direct evidence for generating ROS during decompn. of H2O2 assisted by Ag NPs. Hydroxyl radical formation was obsd. under acidic conditions and was accompanied by dissoln. of Ag NPs. In contrast, evolution of O2 was obsd. in alk. solns. contg. H2O2 and Ag NPs; however, no net dissoln. of Ag NPs was obsd. due to re-redn. of Ag+ as evidenced by a cyclic reaction. Since H2O2 is a biol. relevant product being continuously generated in cells, these results obtained under conditions mimicking different biol. microenvironments may provide insights for finding new biomedical applications for Ag NPs and for risk assessment.
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      Maji, S. K.; Mandal, A. K.; Nguyen, K. T.; Borah, P.; Zhao, Y. Cancer Cell Detection and Therapeutics Using Peroxidase-Active Nanohybrid of Gold Nanoparticle-Loaded Mesoporous Silica-Coated Graphene. ACS Appl. Mater. Interfaces 2015, 7 (18), 9807– 9816,  DOI: 10.1021/acsami.5b01758
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      Cancer Cell Detection and Therapeutics Using Peroxidase-Active Nanohybrid of Gold Nanoparticle-Loaded Mesoporous Silica-Coated Graphene
      Maji, Swarup Kumar; Mandal, Amal Kumar; Nguyen, Kim Truc; Borah, Parijat; Zhao, Yanli
      ACS Applied Materials & Interfaces (2015), 7 (18), 9807-9816CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
      Development of efficient artificial enzymes is an emerging field in nanobiotechnol., since these artificial enzymes could overcome serious disadvantages of natural enzymes. In this work, a new nanostructured hybrid was developed as a mimetic enzyme for in vitro detection and therapeutic treatment of cancer cells. The hybrid (GSF@AuNPs) was prepd. by the immobilization of gold nanoparticles (AuNPs) on mesoporous silica-coated nanosized reduced graphene oxide conjugated with folic acid, a cancer cell-targeting ligand. The GSF@AuNPs hybrid showed unprecedented peroxidase-like activity, monitored by catalytic oxidn. of a typical peroxidase substrate, 3,3',5,5'-tetramethylbenzidine (TMB), in the presence of H2O2. On basis of this peroxidase activity, the hybrid was utilized as a selective, quant., and fast colorimetric detection probe for cancer cells. Finally, the hybrid as a mimetic enzyme was employed for H2O2- and ascorbic acid (AA)-mediated therapeutics of cancer cells. In vitro expts. using human cervical cancer cells (HeLa cells) exhibited the formation of reactive oxygen species (OH• radical) in the presence of peroxidase-mimic GSF@AuNPs with either exogenous H2O2 or endogenous H2O2 generated from AA, leading to an enhanced cytotoxicity to HeLa cells. In the case of normal cells (human embryonic kidney HEK 293 cells), the treatment with the hybrid and H2O2 or AA showed no obvious damage, proving selective killing effect of the hybrid to cancer cells.
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      Chen, Z.; Yin, J. J.; Zhou, Y. T.; Zhang, Y.; Song, L.; Song, M.; Hu, S.; Gu, N. Dual Enzyme-like Activities of Iron Oxide Nanoparticles and Their Implication for Diminishing Cytotoxicity. ACS Nano 2012, 6 (5), 4001– 4012,  DOI: 10.1021/nn300291r
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      Dual Enzyme-like Activities of Iron Oxide Nanoparticles and Their Implication for Diminishing Cytotoxicity
      Chen, Zhongwen; Yin, Jun-Jie; Zhou, Yu-Ting; Zhang, Yu; Song, Lina; Song, Mengjie; Hu, Sunling; Gu, Ning
      ACS Nano (2012), 6 (5), 4001-4012CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Iron oxide nanoparticles (IONPs) are frequently used in biomedical applications, yet their toxic potential is still a major concern. While most studies of biosafety focus on cellular responses after exposure to nanomaterials, little is reported to analyze reactions on the surface of nanoparticles as a source of cytotoxicity. Here we report that different intracellular microenvironment in which IONPs are located leads to contradictive outcomes in their abilities to produce free radicals. We first verified pH-dependent peroxidase-like and catalase-like activities of IONPs and investigated how they interact with hydrogen peroxide (H2O2) within cells. Results showed that IONPs had a concn.-dependent cytotoxicity on human glioma U251 cells, and they could enhance H2O2-induced cell damage dramatically. By conducting ESR spectroscopy expts., we showed that both Fe3O4 and γ-Fe2O3 nanoparticles could catalyze H2O2 to produce hydroxyl radicals in acidic lysosome mimic conditions, with relative potency Fe3O4 > γ-Fe2O3, which was consistent with their peroxidase-like activities. However, no hydroxyl radicals were obsd. in neutral cytosol mimic conditions with both nanoparticles. Instead, they decompd. H2O2 into H2O and O2 directly in this condition through catalase-like activities. Transmission electron micrographs revealed that IONPs located in lysosomes in cells, the acidic environment of which may contribute to hydroxyl radical prodn. This is the first study regarding cytotoxicity based on their enzyme-like activities. Since H2O2 is continuously produced in cells, our data indicate that lysosome-escaped strategy for IONP delivery would be an efficient way to diminish long-term toxic potential.
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      Zhang, C.; Bu, W.; Ni, D.; Zhang, S.; Li, Q.; Yao, Z.; Zhang, J.; Yao, H.; Wang, Z.; Shi, J. Synthesis of Iron Nanometallic Glasses and Their Application in Cancer Therapy by a Localized Fenton Reaction. Angew. Chem., Int. Ed. 2016, 55 (6), 2101– 2106,  DOI: 10.1002/anie.201510031
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      Synthesis of Iron Nanometallic Glasses and Their Application in Cancer Therapy by a Localized Fenton Reaction
      Zhang, Chen; Bu, Wenbo; Ni, Dalong; Zhang, Shenjian; Li, Qing; Yao, Zhenwei; Zhang, Jiawen; Yao, Heliang; Wang, Zheng; Shi, Jianlin
      Angewandte Chemie, International Edition (2016), 55 (6), 2101-2106CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Metallic glasses and cancer theranostics are emerging fields that do not seem to be related to each other. Herein, we report the facile synthesis of amorphous iron nanoparticles (AFeNPs) and their superior physicochem. properties compared to their cryst. counterpart, iron nanocrystals (FeNCs). The AFeNPs can be used for cancer theranostics by inducing a Fenton reaction in the tumor by taking advantage of the mild acidity and the overproduced H2O2 in a tumor microenvironment: Ionization of the AFeNPs enables on-demand ferrous ion release in the tumor, and subsequent H2O2 disproportionation leads to efficient .OH generation. The endogenous stimuli-responsive .OH generation in the presence AFeNPs enables a highly specific cancer therapy without the need for external energy input.
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    50. 50
      Li, W. P.; Su, C. H.; Chang, Y. C.; Lin, Y. J.; Yeh, C. S. Ultrasound-Induced Reactive Oxygen Species Mediated Therapy and Imaging Using a Fenton Reaction Activable Polymersome. ACS Nano 2016, 10 (2), 2017– 2027,  DOI: 10.1021/acsnano.5b06175
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      50
      Ultrasound-Induced Reactive Oxygen Species Mediated Therapy and Imaging Using a Fenton Reaction Activable Polymersome
      Li, Wei-Peng; Su, Chia-Hao; Chang, Yi-Ching; Lin, Yu-Jiung; Yeh, Chen-Sheng
      ACS Nano (2016), 10 (2), 2017-2027CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Ultrasound techniques have been extensively employed for diagnostic purposes. Because of its features of low cost, easy access, and noninvasive real-time imaging, toward clin. practice it is highly anticipated to simply use diagnostic ultrasound to concurrently perform imaging and therapy. We report a H2O2-filled polymersome to display echogenic reflectivity and reactive oxygen species-mediated cancer therapy simply triggered by the microultrasound diagnostic system accompanied by MR imaging. Instead of filling common perfluorocarbons, the encapsulation of H2O2 in H2O2/Fe3O4-PLGA polymersome provides O2 as the echogenic source and •OH as the therapeutic element. On exposure to ultrasound, the polymersome can be easily disrupted to yield •OH through the Fenton reaction by reaction of H2O2 and Fe3O4. We showed that malignant tumors can be completely removed in a nonthermal process.
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      He, Y.; Del Valle, A.; Qian, Y.; Huang, Y. F. Near Infrared Light-Mediated Enhancement of Reactive Oxygen Species Generation through Electron Transfer from Graphene Oxide to Iron Hydroxide/Oxide. Nanoscale 2017, 9 (4), 1559– 1566,  DOI: 10.1039/C6NR08784A
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      Near infrared light-mediated enhancement of reactive oxygen species generation through electron transfer from graphene oxide to iron hydroxide/oxide
      He, Yue; del Valle, Andrea; Qian, Yu; Huang, Yu-Fen
      Nanoscale (2017), 9 (4), 1559-1566CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
      Clin. applications of current photodynamic therapy (PDT) agents are often restricted to be activated only by UV and visible light, which have very poor tissue penetration depths. In this study, a new near IR (NIR)-absorbing nanoagent based on graphene oxide decorated with iron hydroxide/oxide (GO-FeOxH) was developed for light-activated nanomaterial-mediated PDT. This nanocomposite, GO-FeOxH was prepd. via the one-step electrooxidn. of iron nails in an aq. GO soln. The as-prepd. GO-FeOxH showed a much higher reactive oxygen species (ROS) activity under NIR light irradn. than GO. Through a variety of spectroscopic analyses, the mechanism involved in the enhancement of ROS activity of GO by FeOxH was systematically investigated. We obsd. that NIR light irradn. promotes electron transfer from GO to the Fe(III) of FeOxH and accelerates their reaction with O2, forming superoxide anion radicals, which then undergo a disproportionation reaction to produce H2O2. H2O2 then reacts with Fe(II) in FeOxH to mediate Fenton reactions, producing amplified hydroxyl radicals. Using in vitro studies, we demonstrated that GO-FeOxH can be used as a NIR activatable PDT nanoagent, providing efficient cancer therapy.
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    52. 52
      Ranji-Burachaloo, H.; Gurr, P. A.; Dunstan, D. E.; Qiao, G. G. Cancer Treatment through Nanoparticle-Facilitated Fenton Reaction. ACS Nano 2018, 12 (12), 11819– 11837,  DOI: 10.1021/acsnano.8b07635
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      Cancer Treatment through Nanoparticle-Facilitated Fenton Reaction
      Ranji-Burachaloo, Hadi; Gurr, Paul A.; Dunstan, Dave E.; Qiao, Greg G.
      ACS Nano (2018), 12 (12), 11819-11837CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      A review. Currently, cancer is the second largest cause of death worldwide and has reached crit. levels. In spite of all the efforts, common treatments including chemotherapy, photodynamic therapy, and photothermal therapy suffer from various problems which limit their efficiency and performance. For this reason, different strategies are being explored which improve the efficiency of these traditional therapeutic methods or treat the tumor cells directly. One such strategy utilizing the Fenton reaction has been investigated by many groups for the possible treatment of cancer cells. This approach is based on the knowledge that high levels of hydrogen peroxide exist within cancer cells and can be used to catalyze the Fenton reaction, leading to cancer-killing reactive oxygen species. Anal. of the current literature has shown that, due to the diverse morphologies, different sizes, various chem. properties, and the tunable structure of nanoparticles, nanotechnol. offers the most promising method to facilitate the Fenton reaction with cancer therapy. This review aims to highlight the use of the Fenton reaction using different nanoparticles to improve traditional cancer therapies and the emerging Fenton-based therapy, highlighting the obstacles, challenges, and promising developments in each of these areas.
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      Bokare, A. D.; Choi, W. Review of Iron-Free Fenton-like Systems for Activating H2O2 in Advanced Oxidation Processes. J. Hazard. Mater. 2014, 275, 121– 135,  DOI: 10.1016/j.jhazmat.2014.04.054
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      Review of iron-free Fenton-like systems for activating H2O2 in advanced oxidation processes
      Bokare, Alok D.; Choi, Wonyong
      Journal of Hazardous Materials (2014), 275 (), 121-135CODEN: JHMAD9; ISSN:0304-3894. (Elsevier B.V.)
      A review is given. Fe-catalyzed H2O2 decompn. for in situ generation of hydroxyl radicals (HO•) has been extensively developed as advanced oxidn. processes (AOPs) for environmental applications. A variety of catalytic iron species constituting metal salts (in Fe2+ or Fe3+ form), metal oxides (e.g., Fe2O3, Fe3O4), and zero-valent metal (Fe0) have been exploited for chem. (classical Fenton), photochem. (photo-Fenton) and electrochem. (electro-Fenton) degrdn. pathways. However, the requirement of strict acidic conditions to prevent iron pptn. still remains the bottleneck for iron-based AOPs. We present a review of alternative non-Fe Fenton catalysts and their reactivity towards H2O2 activation. Elements with multiple redox states (such as Cr, Ce, Cu, Co, Mn and Ru) all directly decomp. H2O2 into HO• through conventional Fenton-like pathways. The in situ formation of H2O2 and decompn. into HO• can be also achieved using electron transfer mechanism in 0-valent Al/O system. Although these Fenton systems (except Al) work efficiently even at neutral pH, the H2O2 activation mechanism is very specific to the nature of the catalyst and critically depends on its compn. This paper describes the complex mechanisms and emphasizes on practical limitations influencing their environmental applications.
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      Wu, D.; Gao, Y.; Qi, Y.; Chen, L.; Ma, Y.; Li, Y. Peptide-Based Cancer Therapy: Opportunity and Challenge. Cancer Lett. 2014, 351 (1), 13– 22,  DOI: 10.1016/j.canlet.2014.05.002
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      Peptide-based cancer therapy: Opportunity and challenge
      Wu, Dongdong; Gao, Yanfeng; Qi, Yuanming; Chen, Lixiang; Ma, Yuanfang; Li, Yanzhang
      Cancer Letters (New York, NY, United States) (2014), 351 (1), 13-22CODEN: CALEDQ; ISSN:0304-3835. (Elsevier)
      A review. Cancer is one of the leading causes of death worldwide. Conventional cancer therapies mainly focus on mass cell killing without high specificity and often cause severe side effects and toxicities. Peptides are a novel class of anticancer agents that could specifically target cancer cells with lower toxicity to normal tissues, which will offer new opportunities for cancer prevention and treatment. Anticancer peptides face several therapeutic challenges. In this review, we present the sources and mechanisms of anticancer peptides and further discuss modification strategies to improve the anticancer effects of bioactive peptides.
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      Qi, G.-B.; Gao, Y.-J.; Wang, L.; Wang, H. Self-Assembled Peptide-Based Nanomaterials for Biomedical Imaging and Therapy. Adv. Mater. 2018, 30 (22), 1703444,  DOI: 10.1002/adma.201703444
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      Qiao, Z. Y.; Lin, Y. X.; Lai, W. J.; Hou, C. Y.; Wang, Y.; Qiao, S. L.; Zhang, D.; Fang, Q. J.; Wang, H. A General Strategy for Facile Synthesis and in Situ Screening of Self-Assembled Polymer-Peptide Nanomaterials. Adv. Mater. 2016, 28 (9), 1859– 1867,  DOI: 10.1002/adma.201504564
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      A general strategy for facile synthesis and in situ screening of self-assembled polymer-peptide nanomaterials
      Qiao, Zeng-Ying; Lin, Yao-Xin; Lai, Wen-Jia; Hou, Chun-Yuan; Wang, Yi; Qiao, Sheng-Lin; Zhang, Di; Fang, Qiao-Jun; Wang, Hao
      Advanced Materials (Weinheim, Germany) (2016), 28 (9), 1859-1867CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The authors first report a general strategy for facile synthesis and in situs screening of a library of self-assembled polymer-peptide conjugates (PPCs). The high-yield, bio-freiendly chem., and mild reaction conditions fabricate the combinatorial synthesis and screening of therapeutic peptide nanomaterials. The PPCs could self-assemble into nanoparticles in the reaction process and were directly used for cytotoxicy assay without further purifn. This strategy fabricated investigating structure-function relationships of PPC library, and PPCs with optimal structures were prepd. according to the guidelines. The reliability and scalability of this strategy were proved by enhanced cancer therapeutic efficacy in vitro and in vivo. Therefore, the facile approach opened an avenue for rapid synthesis and screening of peptide nanomaterials. By further developing this synthesis and screening approach to incorporate other functional peptides and stimuli sensitive spacers, novel peptide nanomaterials may be found, which have broad application in disease diagnosis and therapy.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVyns73K&md5=3d0ad54be5e02c966671e86b9ffaf2fa
    57. 57
      Wang, Y.; Lin, Y.-X.; Qiao, Z.-Y.; An, H.-W.; Qiao, S.-L.; Wang, L.; Rajapaksha, R. P. Y. J.; Wang, H. Self-Assembled Autophagy-Inducing Polymeric Nanoparticles for Breast Cancer Interference In-Vivo. Adv. Mater. 2015, 27 (16), 2627– 2634,  DOI: 10.1002/adma.201405926
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      Self-assembled autophagy-inducing polymeric nanoparticles for breast cancer interference in-vivo
      Wang, Yi; Lin, Yao-Xin; Qiao, Zeng-Ying; An, Hong-Wei; Qiao, Sheng-Lin; Wang, Lei; Rajapaksha, R. P. Yeshan J.; Wang, Hao
      Advanced Materials (Weinheim, Germany) (2015), 27 (16), 2627-2634CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The authors demonstrated a convenient approach to prepg. self-assembled micelle-like nanoparticles composed of pH-sensitive poly(β-amino ester)s and an autophagy-inducing peptide (Bec1). The P-Bec1 nanoparticles displayed enhanced autophagy-inducing cytotoxicity to MCF-7 cells that are Bec1 deficient, because P-Bec1 can contribute to efficient internalization of the Bec1 peptide into cells by the endocytosis pathway. Moreover, the P-Bec1 nanoparticles effectively induced autophagy and inhibited tumor growth. By modulating the Bec1 peptide autophagy-inducing effect assisted by pH-sensitive polymers, it was identified that the autophagy anticancer efficiency of P-Bec1. It is believed that the P-Bec1 peptide described here provides an important addn. to existing efforts in identifying new cancer therapies, and has a promising effect esp. in autophagy deficiency tumors.
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      Prives, C. Signaling to P53: Breaking Minireview the MDM2–P53 Circuit. Cell 1998, 95 (1), 5– 8,  DOI: 10.1016/S0092-8674(00)81774-2
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      Signaling to p53: breaking the MDM2-p53 circuit
      Prives, Carol
      Cell (Cambridge, Massachusetts) (1998), 95 (1), 5-8CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
      A review, with 27 refs. Current knowledge suggests that diverse upstream signals funnel into a single crit. interaction, namely that between p53 and its neg. regulator, MDM2. The author discusses p53 interactions with MDM2, signaling through covalent modification of p53, the discovery of ARF explaining how oncogenes regulate p53, the complexity of p53 circuitry, and future directions of research.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXmslWmu7k%253D&md5=fcb4b88a31d413d8b841044c72c52d5e
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      Frappier, V.; Duran, M.; Keating, A. E. PixelDB: Protein–Peptide Complexes Annotated with Structural Conservation of the Peptide Binding Mode. Protein Sci. 2018, 27 (1), 276– 285,  DOI: 10.1002/pro.3320
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      PixelDB: Protein-peptide complexes annotated with structural conservation of the peptide binding mode
      Frappier, Vincent; Duran, Madeleine; Keating, Amy E.
      Protein Science (2018), 27 (1), 276-285CODEN: PRCIEI; ISSN:1469-896X. (Wiley-Blackwell)
      PixelDB, the Peptide Exosite Location Database, compiles 1966 non-redundant, high-resoln. structures of protein-peptide complexes filtered to minimize the impact of crystal packing on peptide conformation. The database is organized to facilitate study of structurally conserved vs. non-conserved elements of protein-peptide engagement. PixelDB clusters complexes based on the structural similarity of the peptide-binding protein, and by comparing complexes within a cluster highlights examples of domains that engage peptides using more than one binding mode. PixelDB also identifies conserved peptide core structural motifs characteristic of each binding mode. Peptide regions that flank core motifs often make non-structurally conserved interactions with the protein surface in regions we call exosites. Many examples establish that exosite contacts can be important for enhancing protein binding and interaction specificity. PixelDB provides a resource for computational and structural biologists to study, model, and predict core-motif and exosite-contacting peptide interactions. PixelDB is available to the community without restriction in a convenient flat-file format with accompanying visualization tools.
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    60. 60
      Yan, J.; He, W.; Yan, S.; Niu, F.; Liu, T.; Ma, B.; Shao, Y.; Yan, Y.; Yang, G.; Lu, W.; Du, Y.; Lei, B.; Ma, P. X. Self-Assembled Peptide-Lanthanide Nanoclusters for Safe Tumor Therapy: Overcoming and Utilizing Biological Barriers to Peptide Drug Delivery. ACS Nano 2018, 12 (2), 2017– 2026,  DOI: 10.1021/acsnano.8b00081
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      Self-Assembled Peptide-Lanthanide Nanoclusters for Safe Tumor Therapy: Overcoming and Utilizing Biological Barriers to Peptide Drug Delivery
      Yan, Jin; He, Wangxiao; Yan, Siqi; Niu, Fan; Liu, Tianya; Ma, Bohan; Shao, Yongping; Yan, Yuwei; Yang, Guang; Lu, Wuyuan; Du, Yaping; Lei, Bo; Ma, Peter X.
      ACS Nano (2018), 12 (2), 2017-2026CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Developing a sophisticated nanomedicine platform to deliver therapeutics effectively and safely into tumor/cancer cells remains challenging in the field of nanomedicine. In particular, reliable peptide drug delivery systems capable of overcoming biol. barriers are still lacking. Here, we developed a simple, rapid, and robust strategy to manuf. nanoclusters of ∼90 nm in diam. that are self-assembled from lanthanide-doped nanoparticles (5 nm), two anticancer peptides with different targets (BIM and PMI), and one cyclic peptide iNGR targeted to cancer cells. The peptide-lanthanide nanoclusters (LDC-PMI-BIM-iNGR) enhanced the resistance of peptide drugs to proteolysis, disassembled in response to reductive conditions that are present in the tumor microenvironment and inhibited cancer cell growth in vitro and in vivo. Notably, LDC-PMI-BIM-iNGR exhibited extremely low systemic toxicity and side effects in vivo. Thus, the peptide-lanthanide nanocluster may serve as an ideal multifunctional platform for safe, targeted, and efficient peptide drug delivery in cancer therapy.
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    61. 61
      Tuguntaev, R. G.; Chen, S.; Eltahan, A. S.; Mozhi, A.; Jin, S.; Zhang, J.; Li, C.; Wang, P. C.; Liang, X.-J. P-Gp Inhibition and Mitochondrial Impairment by Dual-Functional Nanostructure Based on Vitamin E Derivatives To Overcome Multidrug Resistance. ACS Appl. Mater. Interfaces 2017, 9 (20), 16900– 16912,  DOI: 10.1021/acsami.7b03877
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      P-gp Inhibition and Mitochondrial Impairment by Dual-Functional Nanostructure Based on Vitamin E Derivatives To Overcome Multidrug Resistance
      Tuguntaev, Ruslan G.; Chen, Shizhu; Eltahan, Ahmed Shaker; Mozhi, Anbu; Jin, Shubin; Zhang, Jinchao; Li, Chan; Liang, Xing-Jie
      ACS Applied Materials & Interfaces (2017), 9 (20), 16900-16912CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
      Vitamin E derivs. possess many essential features for drug-delivery applications, such as biocompatibility, stability, improvement of water soly. of hydrophobic compds., anticancer activity, and the ability to overcome multidrug resistance (MDR). Herein, vitamin E derivs. are used to overcome MDR through a combined P-glycoprotein (P-gp) inhibition and mitochondrial impairment strategy. A novel nanomicellar drug-delivery system as a carrier for doxorubicin (DOX) was developed, in which D-α-tocopheryl polyethylene glycol 1000 succinate was used as a P-gp inhibitor, α-tocopheryl succinate was introduced as a mitochondrial disrupting agent, and D-α-tocopheryl polyethylene glycol 2000 succinate was used as the main building block of micelles. The optimal ratio between the components of the nanocarrier was detd. The resultant DOX-loaded mixed micelles exhibited a suitable size of 52.08 nm, high drug-loading encapsulation efficiency (>98%), high stability, and pH-dependent drug release. In vitro expts. demonstrated a significantly increased cytotoxic activity of DOX-loaded mixed micelles against resistant MCF-7/Adr cells (45-fold higher than DOX after 48 h of treatment). In vivo studies revealed superior antitumor efficiency with less cardio- and hepatotoxicities of DOX-loaded micelles compared with that of free DOX. These results highlight that the developed DOX-loaded mixed micelles have a promising potential to overcome MDR in chemotherapy for clin. usage.
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      Dai, Z.; Yao, Q.; Zhu, L. MMP2-Sensitive PEG-Lipid Copolymers: A New Type of Tumor-Targeted P-Glycoprotein Inhibitor. ACS Appl. Mater. Interfaces 2016, 8 (20), 12661– 12673,  DOI: 10.1021/acsami.6b03064
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      62
      MMP2-Sensitive PEG-Lipid Copolymers: A New Type of Tumor-Targeted P-Glycoprotein Inhibitor
      Dai, Zhi; Yao, Qing; Zhu, Lin
      ACS Applied Materials & Interfaces (2016), 8 (20), 12661-12673CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
      Low tumor targetability and multidrug resistance (MDR) are two major impediments to the success of cancer treatments. Nanomaterials which possess high tumor targetability and the ability to reverse the MDR are rare. This report describes a new type of self-assembling polyethylene glycol-phosphoethanolamine-based copolymers (PEG-pp-PE) which showed both the matrix metalloproteinase 2 (MMP2)-sensitive tumor-targeted drug delivery and ability to inhibit the P-glycoprotein (P-gp)-mediated drug efflux. In this study, we synthesized a series of the homologous analogs of PEG-pp-PE copolymers and investigated the influence of their structures, including PEG lengths and peptide linkers, on the drug efflux, and identified the underlying mechanisms. We found that the whole structure (PEG-peptide-lipid) rather than any parts of the copolymers was key for the P-gp inhibition and a delicate balance between the hydrophilic and lipophilic segments of the PEG-pp-PE copolymers was needed for better modulating the P-gp-mediated drug efflux. The best copolymer, PEG2k-pp-PE, showed even higher P-gp inhibition effect than the D-α-tocopherol polyethylene glycol 1000 succinate (TPGS1k). We also found that the P-gp inhibition capability of PEG-pp-PE copolymers was highly assocd. with the P-gp down-regulation, the increase in the plasma membrane fluidity, and the inhibition of the P-gp ATPase activity. Besides, the excellent physicochem. properties, high drug loading, MMP2-dependent drug release, and improved drug efficacy in the MDR cancer cells suggested that the PEG-pp-PE copolymers might have great potential for building tumor-targeted drug delivery systems for treating drug-resistant cancers.
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      Kou, L.; Sun, R.; Bhutia, Y. D.; Yao, Q.; Chen, R. Emerging Advances in P-Glycoprotein Inhibitory Nanomaterials for Drug Delivery. Expert Opin. Drug Delivery 2018, 15 (9), 869– 879,  DOI: 10.1080/17425247.2018.1517749
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      Emerging advances in P-glycoprotein inhibitory nanomaterials for drug delivery
      Kou, Longfa; Sun, Rui; Bhutia, Yangzom D.; Yao, Qing; Chen, Ruijie
      Expert Opinion on Drug Delivery (2018), 15 (9), 869-879CODEN: EODDAW; ISSN:1742-5247. (Taylor & Francis Ltd.)
      A review. : P-glycoprotein 1 (P-gp) pumps out many foreign/toxic substances out of the cells, including intracellular drugs, causing multidrug resistance (MDR) and chemotherapy failure. It remains quite a challenge to inhibit P-gp to combat MDR and improve cellular bioavailability since it requires efficient inhibitors along with adequate formulation strategy. Lately, nanocarriers are gaining much attention and form an attractive platform for delivering drugs into cells. Therefore, nanomaterials act as direct inhibitors of P-gp will be an attractive alternative to overcome MDR.: This paper reviews the most recent advances on those nanomaterials that are currently in the developmental stage and has proven useful to treat P-gp involved MDR. Also, we emphasize those emerging multifunctional nanomaterials that can construct 'smart' carriers for both tumor targeting and P-gp inhibition. Furthermore, the mechanisms behind P-gp inhibition and the nanoformulation strategies for drug delivery are also discussed.: In light of these updated reports, this review here seeks to suggest an alternative for the chemoresistant cases, and also bring about new thoughts on tackling P-gp concerned drug delivery issues. New advances in nanomaterials with P-gp inhibition are expected to broaden nanopharmaceutics and traditional chemotherapy applications in the coming years.
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      Li, D.; Hu, X.; Zhang, S. Biodegradation of Graphene-Based Nanomaterials in Blood Plasma Affects Their Biocompatibility, Drug Delivery, Targeted Organs and Antitumor Ability. Biomaterials 2019, 202, 12– 25,  DOI: 10.1016/j.biomaterials.2019.02.020
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      64
      Biodegradation of graphene-based nanomaterials in blood plasma affects their biocompatibility, drug delivery, targeted organs and antitumor ability
      Li, Dandan; Hu, Xiangang; Zhang, Suyan
      Biomaterials (2019), 202 (), 12-25CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
      The extensive use of graphene-family nanomaterials (GFNs) in biomedicine and other fields has intentionally or unintentionally resulted in their introduction into the blood circulation system, but the effects of the biotransformation of GFNs in blood plasma on their biocompatibility, organ targeting, drug delivery and antitumor ability remain unclear. The present work discovered that GFN sheets were degraded in human blood plasma to holey sheets and arom. hydrocarbons. The carbon atoms connected with oxygen-contg. groups in the planes of GFNs were the initial attack sites for active substances (e.g., ·OH and O·-2) in blood plasma. Subsequently, C-C/C=C bonds were broken. The reaction rate depended strongly on the extent of oxidization of GFNs. The pristine GFNs caused secondary structure damage to proteins and disturbances of cellular metabolic pathways. In contrast, the biotransformed nanomaterials presented high biocompatibility and were located in and targeted different tissues from their pristine forms, which influenced specific organ targeting therapy. The biotransformed nanomaterials also exhibited higher efficiencies of drug delivery (drug release and location) and killing tumor cells in vitro and in vivo. These findings provide insights into the application of nanomaterials in human healthcare using biotransformed nanomaterials.
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      Law, B. Y. K.; Qu, Y. Q.; Mok, S. W. F.; Liu, H.; Zeng, W.; Han, Y.; Gordillo-Martinez, F.; Chan, W. K.; Wong, K. M. C.; Wong, V. K. W. New Perspectives of Cobalt Tris(Bipyridine) System: Anti-Cancer Effect and Its Collateral Sensitivity towards Multidrug-Resistant (MDR) Cancers. Oncotarget 2017, 8 (33), 55003– 55021,  DOI: 10.18632/oncotarget.18991
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      65
      New perspectives of cobalt tris(bipyridine) system: anti-cancer effect and its collateral sensitivity towards multidrug-resistant (MDR) cancers
      Law Betty Yuen Kwan; Qu Yuan Qing; Mok Simon Wing Fai; Zeng Wu; Han Yu; Gordillo-Martinez Flora; Chan Wai-Kit; Wong Vincent Kam Wai; Liu Hauwei; Wong Keith Man-Chung
      Oncotarget (2017), 8 (33), 55003-55021 ISSN:.
      Platinating compounds including cisplatin, carboplatin, and oxaliplatin are common chemotherapeutic agents, however, patients developed resistance to these clinical agents after initial therapeutic treatments. Therefore, different approaches have been applied to identify novel therapeutic agents, molecular mechanisms, and targets for overcoming drug resistance. In this study, we have identified a panel of cobalt complexes that were able to specifically induce collateral sensitivity in taxol-resistant and p53-deficient cancer cells. Consistently, our reported anti-cancer functions of cobalt complexes 1-6 towards multidrug-resistant cancers have suggested the protective and non-toxic properties of cobalt metal-ions based compounds in anti-cancer therapies. As demonstrated in xenograft mouse model, our results also confirmed the identified cobalt complex 2 was able to suppress tumor growth in vivo. The anti-cancer effect of the cobalt complex 2 was further demonstrated to be exerted via the induction of autophagy, cell cycle arrest, and inhibition of cell invasion and P-glycoprotein (P-gp) activity. These data have provided alternative metal ion compounds for targeting drug resistance cancers in chemotherapies.
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      Jiang, W.; Yin, L.; Chen, H.; Paschall, A. V.; Zhang, L.; Fu, W.; Zhang, W.; Todd, T.; Yu, K. S.; Zhou, S.; Zhen, Z.; Butler, M.; Yao, L.; Zhang, F.; Shen, Y.; Li, Z.; Yin, A.; Yin, H.; Wang, X.; Avci, F. Y.; Yu, X.; Xie, J. NaCl Nanoparticles as a Cancer Therapeutic. Adv. Mater. 2019, 31 (46), 1904058,  DOI: 10.1002/adma.201904058
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      NaCl nanoparticles as a cancer therapeutic
      Jiang, Wen; Yin, Lei; Chen, Hongmin; Paschall, Amy Victoria; Zhang, Liuyang; Fu, Wenyan; Zhang, Weizhong; Todd, Trever; Yu, Kevin Shengyang; Zhou, Shiyi; Zhen, Zipeng; Butler, Michael; Yao, Li; Zhang, Feng; Shen, Ye; Li, Zibo; Yin, Amelia; Yin, Hang; Wang, Xianqiao; Avci, Fikri Y.; Yu, Xiaozhong; Xie, Jin
      Advanced Materials (Weinheim, Germany) (2019), 31 (46), 1904058CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Many inorg. nanoparticles are prepd. and their behaviors in living systems are investigated. Yet, common electrolytes such as NaCl are left out of this campaign. The underlying assumption is that electrolyte nanoparticles will quickly dissolve in water and behave similarly as their constituent salts. Herein, this preconception is challenged. The study shows that NaCl nanoparticles (SCNPs) but not salts are highly toxic to cancer cells. This is because SCNPs enter cells through endocytosis, bypassing cell regulations on ion transport. When dissolved inside cancer cells, SCNPs cause a surge of osmolarity and rapid cell lysis. Interestingly, normal cells are much more resistant to the treatment due to their relatively low sodium levels. Unlike conventional chemotherapeutics, SCNPs cause immunogenic cell death or ICD. In vivo studies show that SCNPs not only kill cancer cells, but also boost an anticancer immunity. The discovery opens up a new perspective on nanoparticle-based therapeutics.
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      Nagy, I. Z.; Lustyik, G.; Nagy, V. Z.; Zarándi, B.; Bertoni-Freddari, C. Intracellular Na+:K+ Ratios in Human Cancer Cells as Revealed by Energy Dispersive X-Ray Microanalysis. J. Cell Biol. 1981, 90 (3), 769– 777,  DOI: 10.1083/jcb.90.3.769
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      Intracellular sodium-potassium ratios in human cancer cells as revealed by energy dispersive x-ray microanalysis
      Nagy, I. Z.; Lustyik, G.; Nagy, V. Z.; Zarandi, B.; Bertoni-Freddari, C.
      Journal of Cell Biology (1981), 90 (3), 769-77CODEN: JCLBA3; ISSN:0021-9525.
      Intranuclear Na+, K+, and Cl- contents were measured by energy-dispersive x-ray microanal. in freeze-fractured, freeze-dried, bulk-tumor samples taken from 10 patients suffering from invasive urogenital cancers. Human biopsies were carried out during the first diagnostic interventions before any cytostatic treatment had been applied. Pathohistol. diagnosis established the malignancy in each case. The cancers were classified as keratinizing, transitional cell, or hypernephroid carcinoma. More than 250 cell nuclei were measured from each type of cancer. The results were compared with those obtained in intact human urothelium taken from patients having no malignant processes. Proximal and distal tubular epithelial cell nuclei representing the origin of human hypernephroid cancer were also measured in rat kidney because corresponding healthy human material cannot be obtained. In all 3 types of cancer cells, the av. intranuclear Na+ content was increased >3-fold and the K+ content was decreased by 32, 16, and 13%, resp. The Cl- content increased, but to a lesser extent than Na+. The intranuclear Na+:K+ ratios were >5-fold higher in the cancer cells on the av., and their distribution histograms were much broader than in the normal human urothelium and in the tubular cell nuclei of the rat kidney. Sustained depolarization of the cell membrane may have a mitogenic effect.
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      Galvez, A.; Morales, M. P.; Eltit, J. M.; Ocaranza, P.; Carrasco, L.; Campos, X.; Sapag-Hagar, M.; Díaz-Araya, G.; Lavandero, S. A Rapid and Strong Apoptotic Process Is Triggered by Hyperosmotic Stress in Cultured Rat Cardiac Myocytes. Cell Tissue Res. 2001, 304 (2), 279– 285,  DOI: 10.1007/s004410100358
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      A rapid and strong apoptotic process is triggered by hyperosmotic stress in cultured rat cardiac myocytes
      Galvez, Anita; Morales, Maria Paz; Eltit, Jose Miguel; Ocaranza, Paula; Carrasco, Loreto; Campos, Ximena; Sapag-Hagar, Mario; Diaz-Araya, Guillermo; Lavandero, Sergio
      Cell & Tissue Research (2001), 304 (2), 279-285CODEN: CTSRCS; ISSN:0302-766X. (Springer-Verlag)
      In all cell types, the maintenance of normal cell vol. is an essential homeostatic function. Relatively little is known about the induction of apoptosis by hyperosmotic stress and its mol. mechanism in terminally differentiated cardiac myocytes. We compared the apoptotic response of cultured neonatal rat cardiomyoctes to hyperosmotic stress by sorbitol (SOR) with those induced by doxorubicin (Doxo) or angiotensin II (Ang II). We also examd. the apoptotic-signaling pathway stimulated by the hyperosmotic stress. Apoptosis was assessed by the observation of: (1) cell viability, (2) DNA fragmentation detected by the TUNEL method and by agarose gel electrophoresis, and (3) poly(ADP-ribose)polymerase (PARP) degrdn., and Bcl-XS and Bcl-XL levels by Western blot anal. Exposure of cardiomyocytes to 0.3 M SOR for 24 h resulted in decreased cell viability and increased generation of oligosomal DNA fragments (2.5-fold of controls). At this time, 83±5% of SOR-treated myocytes were TUNEL-pos. (vs 23.7±6.8% in controls;P<0.01). PARP levels also decreased by approx. 42% when cardiac myocytes were exposed to SOR. Hyperosmotic stress induced a more rapid and stronger apoptotic response in cardiomyocytes than Doxo or Ang II. In addn., SOR increased 3.2-fold Bcl-XS proapoptotic protein without changes in Bcl-XL antiapoptotic protein levels and in the p53-transactivating activity. Taken together, these results strongly suggest that hyperosmotic stress triggers cardiac myocyte apoptosis in a p53-independent manner, being earlier and stronger than apoptosis induced by Doxo and Ang II.
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      Poon, W.; Zhang, Y.-N.; Ouyang, B.; Kingston, B. R.; Wu, J. L. Y.; Wilhelm, S.; Chan, W. C. W. Elimination Pathways of Nanoparticles. ACS Nano 2019, 13 (5), 5785– 5798,  DOI: 10.1021/acsnano.9b01383
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      69
      Elimination Pathways of Nanoparticles
      Poon, Wilson; Zhang, Yi-Nan; Ouyang, Ben; Kingston, Benjamin R.; Wu, Jamie L. Y.; Wilhelm, Stefan; Chan, Warren C. W.
      ACS Nano (2019), 13 (5), 5785-5798CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Understanding how nanoparticles are eliminated from the body is required for their successful clin. translation. Many promising nanoparticle formulations for in vivo medical applications are large (>5.5 nm) and nonbiodegradable, so they cannot be eliminated renally. A proposed pathway for these nanoparticles is hepatobiliary elimination, but their transport has not been well-studied. Here, we explored the barriers that detd. the elimination of nanoparticles through the hepatobiliary route. The route of hepatobiliary elimination is usually through the following pathway: (1) liver sinusoid, (2) space of Disse, (3) hepatocytes, (4) bile ducts, (5) intestines, and (6) out of the body. We discovered that the interaction of nanoparticles with liver nonparenchymal cells (e.g., Kupffer cells and liver sinusoidal endothelial cells) dets. the elimination fate. Each step in the route contains cells that can sequester and chem. or phys. alter the nanoparticles, which influences their fecal elimination. We showed that the removal of Kupffer cells increased fecal elimination by >10 times. Combining our results with those of prior studies, we can start to build a systematic view of nanoparticle elimination pathways as it relates to particle size and other design parameters. This is crit. to engineering medically useful and translatable nanotechnologies.
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      Blanco, E.; Shen, H.; Ferrari, M. Principles of Nanoparticle Design for Overcoming Biological Barriers to Drug Delivery. Nat. Biotechnol. 2015, 33 (9), 941– 951,  DOI: 10.1038/nbt.3330
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      Principles of nanoparticle design for overcoming biological barriers to drug delivery
      Blanco, Elvin; Shen, Haifa; Ferrari, Mauro
      Nature Biotechnology (2015), 33 (9), 941-951CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)
      Biol. barriers to drug transport prevent successful accumulation of nanotherapeutics specifically at diseased sites, limiting efficacious responses in disease processes ranging from cancer to inflammation. Although substantial research efforts have aimed to incorporate multiple functionalities and moieties within the overall nanoparticle design, many of these strategies fail to adequately address these barriers. Obstacles, such as nonspecific distribution and inadequate accumulation of therapeutics, remain formidable challenges to drug developers. A reimagining of conventional nanoparticles is needed to successfully negotiate these impediments to drug delivery. Site-specific delivery of therapeutics will remain a distant reality unless nanocarrier design takes into account the majority, if not all, of the biol. barriers that a particle encounters upon i.v. administration. By successively addressing each of these barriers, innovative design features can be rationally incorporated that will create a new generation of nanotherapeutics, realizing a paradigmatic shift in nanoparticle-based drug delivery.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVymt73I&md5=d693b4429d7ad4cc8b3898f7a0fb6235
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      In the field of nanomedicine, gas therapy is currently a hot topic under exploration as it can treat a variety of disease conditions. The key challenge of delivering medicinal gas via any delivery system is that the technique should be feasible to deliver the gas over an appropriate time interval as well as specifically targeting the affected area. This has enabled gas therapy as an active research area with an aim to improve and discover new materials, methodologies and technologies. In this review, we present the recent advances in research on delivering medicinal gases using nanocarriers that can specifically target with precise spatial-temporal control of release behavior and discuss their future perspectives. The main emphasis has been focused on nanoparticle gas carriers to overcome the challenges in gas delivery for therapeutic applications including prevention of gas diffusion while transportation, improving the stability of the gas in the complex biol. environment, specifically targeting the tissue and controlled gas release for efficient programmed treatment modality. Furthermore, the therapeutic effects of the nanomaterial gas carriers via efficient gas releasing properties demonstrated in the preclin. studies with cell/animal models are discussed. This crit. review is intended to make clear the present status, the possibility and future advancement of gas therapy for the scientific community.
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      A quantum mech. treatment was applied to the Watson-Crick model for DNA. Since the protons are not considered as classical particles but as wave packets, the genetic proton-electron pair code cannot be 100% stable. Due to the quantummech. tunnel effect, there is always a small but finite probability that the protons will change place, alter the genetic code, and give rise to somatic mutations. The latter may be responsible for the phenomenon of aging, as well as for the occurrence of spontaneous tumors and cancer. 23 references.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2cXltlyltw%253D%253D&md5=f0fb24b4fb3fae3228f6b2b7c3c4c738
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