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Clickable Polymer Ligand-Functionalized Iron Oxide Nanocubes: A Promising Nanoplatform for ‘Local Hot Spots’ Magnetically Triggered Drug Release

Cite this: ACS Appl. Mater. Interfaces 2022, 14, 43, 48476–48488
Publication Date (Web):October 18, 2022
https://doi.org/10.1021/acsami.2c14752

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Exploiting the local heat on the surface of magnetic nanoparticles (MNPs) upon exposure to an alternating magnetic field (AMF) to cleave thermal labile bonds represents an interesting approach in the context of remotely triggered drug delivery. Here, taking advantages of a simple and scalable two-step ligand exchange reaction, we have prepared iron oxide nanocubes (IONCs) functionalized with a novel multifunctional polymer ligand having multiple catechol moieties, furfuryl pendants, and polyethylene glycol (PEG) side chains. Catechol groups ensure a strong binding of the polymer ligands to the IONCs surface, while the PEG chains provide good colloidal stability to the polymer-coated IONCs. More importantly, furfuryl pendants on the polymer enable to click the molecules of interest (either maleimide–fluorescein or maleimide–doxorubicin) via a thermal labile Diels–Alder adduct. The resulting IONCs functionalized with a fluorescein/doxorubicin-conjugated polymer ligand exhibit good colloidal stability in buffer saline and serum solution along with outstanding heating performance in aqueous solution or even in viscous media (81% glycerol/water) when exposed to the AMF of clinical use. The release of conjugated bioactive molecules such as fluorescein and doxorubicin could be boosted by applying AMF conditions of clinical use (16 kAm–1 and 110 kHz). It is remarkable that the magnetic hyperthermia-mediated release of the dye/drug falls in the concentration range 1.0–5.0 μM at an IONCs dose as low as 0.5 gFe/L and at no macroscopical temperature change. This local release effect makes this magnetic nanoplatform a potential tool for drug delivery with remote magnetic hyperthermia actuation and with a dose-independent action of MNPs.

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Introduction

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Magnetic nanoparticles (MNPs) hold tremendous potentials for diagnostic and therapeutic applications. Having unique magnetic properties, MNPs were extensively exploited as magnetic resonance imaging (MRI) contrast agents and smart drug delivery systems. (1−5) More recently, the emerging applications of MNPs include their use as tracers in magnetic particle imaging (MPI) and as heat agents in magnetic hyperthermia (MHT) for cancer diagnosis and therapy. (6−8) MHT relies on the exploitation of MNPs as magneto-heat transducers to convert the energy from an alternating magnetic field (AMF) into heat, thus raising the temperature at the side at which MNPs are deposited. (4,6,9,10) The heat can be used to either induce a direct damage to the tumor or to synergize with other therapies, thus achieving a better treatment outcome. (8) In order to avoid eddy currents in healthy tissues, the product of field intensity and frequency (H·f) has to be lower than 5 × 109 A·m–1·s–1. (9−12)
In the context of drug delivery, the heat generated from MNPs during MHT has been considered as a promising stimulus to trigger the release of loaded molecules. (4) Following this approach, drug molecules were linked to the MNP surface via thermal sensitive bonds that could be disrupted at either macroscopic (in the whole media) or local (only vicinal to the MNP surface) temperature changes, the latter also known as the “hot-spot” effect. (6,9,13−16) Oncotherapy based on MHT treatment at 43–46 °C and at an increased temperature for heat-mediated drug delivery requires a sufficient accumulation of MNPs to ensure that the collective heat dissipation reaches the therapeutic temperature range. Therefore, in these cases, only intratumoral nanoparticle deposition enables to reach a therapeutic dose of MNPs, achieving MHT-mediated temperature increase in the therapeutic range (43–46 °C). Alternatively, considering the local heat effect to release a drug associated to a magnetic nanoplatform is a promising strategy for the systemic administration of the drug, as only a tiny fraction of the injected MNPs homes to tumor, and the drug release will not be triggered by the macroscopic temperature rise, but it will rely on the local MNP heat. (17−21) Thanks to their thermosensitive feature, Diels–Alder adducts and diazo compounds have been mainly proposed and exploited as linkers to bind the drug molecules to the MNP surface. (19,22−25) Diazo compounds were widely used as initiators for radical polymerization as they thermally decompose to generate radicals. (26−28) Interestingly, the decomposing/cleaving temperature can be tuned to values as low as 40 °C by modifying the azo chemical structures. (28,29) However, handling such compounds is challenging due to their light and temperature sensitivities. In addition, multiple synthetic steps are required to introduce such a linkage between drug molecules and the MNP surface. In contrast, Diels–Alder adducts are employed as chemicals in “click” reactions for materials chemistry and polymer chemistry. (30−33) This click reaction between diene compounds and dienophile can be carried out at ambient temperature without the need of any catalysts, reaching a quantitative yield. Although the cleaving temperatures of the Diels–Alder adduct (retro-reaction) are rather high (ca. 100 °C) with respect to diazo compounds, a suitable choice of diene and dienophile can decrease the cleaving temperature. (34−37) Indeed, several studies have shown that the endo adduct between furfuryl and maleimide is cleavable at a temperature as low as 60 °C. (36,37) Moreover, as shown by different groups, during MHT, the temperature at the surface of MNPs was much higher than that of the surrounding media, generating a “hot-spot” effect that induced the breakage of some bonds and triggered the drug release. (8,19) More specifically, N’guyen and co-workers demonstrated the release of rhodamine (as a drug model) linked via furfuryl–maleimide adducts to the surface of iron oxide nanoparticles by using MHT without the need for a rise of macroscopic temperature. (22) Despite showing the proof of concept for the AMF-triggered release, the reported magnetic nanocarriers based on diazo or furfuryl–maleimide adducts suffered a low heating performance. Indeed, for these studies, spherical iron oxide MNPs displaying modest SAR values were initially employed as the heat transducers. (18,19,22,25) As such, the release of the loaded drug was shown only under AMF conditions, out of the clinical and safe range, making the translation of such systems not feasible to the clinic. In addition, the ligand motif used in this study contains only one furfuryl group per ligand molecule, thus enabling the binding of a limited number of dye molecules. This, in turn, results in a low amount of dyes/drugs that can be loaded to the NP surface. Eventually, a sufficient dose of dye molecules was released when using a rather high concentration of Fe (1.75 g·L–1). (22,24,25)
Therefore, the development of a high-quality magnetic nanoplatform based on MNPs featuring high SAR values plays a central role for the clinical translation of MHT hot-spot-mediated release systems. Among these, iron oxide nanoparticles of cubic shape, the IONCs employed here, represent one of the promising candidates. Thanks to their magnetic properties strictly related to their unique cubic shape, IONCs exhibits 1 order magnitude higher SAR values with respect to the spherical nanoparticles of the same magnetic volume. (38,39) The IONCs chosen here were also proved to work as heat transducers for MHT and heat-mediated drug delivery in in vivo models reaching the therapeutic temperature at an iron dose that was 1 order of magnitude lower than that of spherical iron oxide NPs. (14,38−40) Besides the magnetic properties of the magnetic core, surface ligands have a great impact to ensure the stability of MNPs in physiological conditions and in turn to affect their heating capability which strongly depends on the IONCs colloidal stability and aggregation state. (33,41−47) Block polymers, owing to their macromolecular structure, can serve as a versatile and robust platform to provide multiple functions of interest. (43) For instance, the polymer structure can be tailored to bear several surface coordination moieties to anchor the nanoparticle surface, also known as multidentate, which helps to improve the stability of NPs in physiological conditions by reducing the ligand detachment. Modified polymers bearing catechol groups, such as poly(acrylic acid) (PAA) and poly(isobutylene-co-maleic anhydride) (PIMA) derivates, have a high affinity for iron oxide-rich surface. (43,48−52) However, synthetic approaches using these polymers suffer some drawbacks. For PAA, the introduction of catechol and other functional groups, that is, polyethylene glycol (PEG), was done by the reaction of the carboxylic acid group of the polymer toward primary amine-derived molecules using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) coupling chemistry which is not efficient and selective. The ring opening reaction between the anhydride in PIMA and primary amine is more reactive and selective, but it generally results in the formation of carboxylic acid groups on the resulting ligand structure. (43,48,51,52) Moreover, these commercial polymers are often synthesized by means of free radical polymerization, thus limiting the chances to tune their degree of polymerization, and the polymer chains are not uniform, represented by a high dispersity (Đ) index of 3 to 4. In this respect, using activated ester-based polymer synthesized by living radical polymerization would be more advantageous. Recently, we have shown that the copolymer of N-succinimidyl methacrylate (NSMA) and polyethylene glycol methacrylate represents a robust and versatile precursor to synthesize PEGylated multidentate ligands for water transfer of inorganic nanoparticles. (53) With the ester NSMA pendants being activated, different anchoring groups can be introduced in a selective and efficient manner. As the polymer precursor already has PEG side chains, the post-synthesis reaction to introduce PEG molecules can be skipped, thus reducing the complexity of the synthetic pathway.
In this study, we report a magnetic nanocarrier based on IONCs (17 ± 2 nm) and a multifunctional polymer that can load and release fluorescein dye, chosen as a drug model, or doxorubicin (Doxo) as a chemotherapeutic agent by means of retro Diels–Alder reaction and under clinically relevant MHT field conditions. Taking advantage of the one-pot reaction between well-defined poly(N-succinimidyl methacrylate-co-polyethylene glycol methacrylate), P(NSMA-co-PEGMA), and dopamine, furfuryl amine, and PEG chains bearing either carboxylic acid (−COOH)- or azide (−N3)-terminated groups, we synthesize a versatile and robust polymer ligand (PEG-CF-COOH) bearing several catechol (C) and furfuryl (F) moieties along with functional PEG-COOH pendants. On the other hand, by the reaction of P(NSMA-co-PEGMA) with dopamine, furfuryl amine, and amine-PEG chains bearing azide (−N3)-terminated groups, a PEG-CF-N3 polymer platform was made.
The furfuryl pendants of PEG-CF-COOH reacted with maleimide-derived fluorescein to yield PEG-CFluo-COOH, while PEG-CF-N3 was conjugated with maleimide-derived Doxo to yield PEG-CDoxo-N3. The surface of IONCs was primed with the developed ligands using a simple and scalable two-step ligand exchange procedure. Here, surfactant-coated IONCs were first treated with tetramethylammonium hydroxide (TMAOH) to transfer the nanocubes into water and temporarily stabilize them by charge repulsion. Next, in the presence of sodium carbonate as a nontoxic base, the addition of the aqueous soluble PEG-CDoxo-N3 or PEG-CFluo-COOH to the surface of IONCs enables the ligand exchange of TMAOH molecules with our developed ligands. The SAR values of IONCs upon water transfer are comparable to those values reported in the literature for the same IONCs coated by other polymers. Moreover, they remain colloidally stable in serum solution until 8 days. Most importantly, it was demonstrated here that at clinical MHT conditions as mild as 110 kHz and 16 kA·m–1, the release of doxorubicin and fluorescein dye was achieved with a negligible change of macroscopic temperature and with a less dependence on the nanoparticle concentration in solution.

Results and Discussion

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The synthesis of PEGylated multidentate ligand bearing several furfuryl groups was aimed, taking advantages of photo-induced atom transfer radical polymerization (Photo-ATRP) of activated ester methacrylate, followed by the aminolysis reaction (Scheme 1). Initially, a poly(N-succinimidyl methacrylate-co-polyethylene glycol methacrylate), P(NSMA-co-PEGMA), was synthesized by the copolymerization reaction of N-succinimidyl methacrylate and polyethylene glycol methacrylate using the Photo-ATRP technique, as described in our previous work (see also Scheme S1 of the Supporting Information). (53) Here, a molar feeding ratio [NSMA]:[PEGMA]:[Initiator] of 12:8:1 was used. After the reaction time, the polymerization solution was passed through a column of aluminum oxide to remove the copper catalyst, followed by precipitation in diethyl ether to remove the unreacted reagents. The obtained polymer was characterized by 1H NMR, and the characteristic proton peaks of succinimidyl (s) and PEG pendants (p,q) can be clearly identified, indicating a successful polymerization step (Figure 1A). By comparing the integration peaks between the phenyl group of the initiator (a) and the methylene group (p) of PEG and the one of succinimidyl (s), a degree of polymerization of 26 and a molar percentage of NSMA of 54% were determined. Size exclusion chromatography (SEC) revealed a molar mass of 13,500 g·mol–1 along with a low dispersity (Đ) of 1.25, indicating that the polymerization occurred in a controlled manner.

Figure 1

Figure 1. Characterization of multidentate and functional polymers by 1H NMR. 1H NMR spectra (with the assignments of the characteristic peaks) of P(PEGMA-co-NSMA) (A); polymer precursor upon the reaction with NH2-PEG-N3, furfurylamine, and dopamine hydrochloride (PEG-CF-N3) (B); and multifunctional PEGylated polymeric ligand (PEG-CDoxo-N3) after the reaction between PEG-CF-N3 and maleimide-derived doxorubicin (C); and (D) multifunctional PEGylated polymeric ligand (PEG-CFluo-COOH) after the reaction between PEG-CF-COOH and maleimide-derived fluorescein. The measurements were done using deuterated DMSO as the solvent.

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Scheme 1

Scheme 1. Representative Synthetic Approach To Prepare Multifunctional PEGylated Polymeric Ligands Using Activated Ester Methacrylate-Based Polymers and Diels–Alder Click Chemistry
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aPoly(polyethylene glycol methacrylate-co-N-succinimidyl methacrylate), P(PEGMA-co-NSMA), is used as a reactive precursor to introduce functional PEG, catechol, and furfuryl pendants by means of a one-pot aminolysis reaction, followed by the conjugation of biomolecules such as maleimide-derived fluorescein (Fluo) or maleimide-derived doxorubicin (Doxo) by Diels–Alder click chemistry.

Next, P(PEGMA-co-NSMA) was used as a precursor to synthesize two types of multifunctional polymers, PEG-CF-COOH and PEG-CF-N3 as shown in Scheme 1. Here, a longer PEG spacer (Mw of 3000 g·mol–1) was introduced by first carrying out the reaction of P(PEGMA-co-NSMA) with NH2-PEG-COOH.HCl amino-PEG, followed by the reaction with furfuryl amine (FA) and dopamine (DOPA.HCl) in a one-pot reaction to yield PEG-CF-COOH. The molar ratio between NH2-PEG-COOH and NSMA was kept at 1:7, while both FA and DOPA.HCl (anchored via the amino group on the molecules) were used in excess with respect to NSMA (2:1 molar ratio for both). For the production of the PEG-CF-N3 polymer ligand, an identical procedure and molar ratios of FA and DOPA.HCl to NSMA were used, except for the replacement of NH2-PEG-COOH.HCl with NH2-PEG-N3, having the same molar mass of 3000 gmol and at the same molar ratio with respect to NSMA. Once these ligands are anchored on the surface of IONCs, the existence of either carboxylic acid or azide groups will offer the possibility to modify with other functional groups such as targeting moieties and/or imaging agents. Both PEG-CF-COOH and PEG-CF-N3 were purified by intensive dialysis against 0.01 M HCl solution and final dialysis against MilliQ water prior to the characterization by 1H NMR. It was observed that the pH of media used for dialysis had an important role on the purity of the resulting polymer ligands. Indeed, when an aqueous solution at pH 7.4 was used as the medium, the dialysates turned quickly to a reddish color, indicating the self-polymerization of excess dopamine in a basic aqueous solution (data not shown). The reaction seemed to be even further pushed by the addition of TEA, which switched the pH of the media to more basic values. 1H NMR performed on the dialysate (after three cycles of dialyzing against water) also revealed the characteristic peaks of poly(dopamine) (8.50 to 7.50 ppm) (Figure S1). Therefore, to avoid the self-polymerization of dopamine, a diluted acidic water solution (HCl 0.01 N) was chosen as the dialyzing medium because at this pH, no change in solution color and no other sign of self-polymerization of dopamine were observed.
Figure 1B depicts the 1H NMR spectrum of PEG-CF-N3 in which all the characteristic resonances of the polymer can be verified. The retraction of the N-succinimidyl signal (Figure 1A,s) along with the appearance of amide proton (Figure 1B,i) verified the successful reactions between P(PEGMA-co-NSMA) and the amino derivatives. By comparing the integration peaks between the primary amide protons i (furfuryl), n (dopamine), u (PEG-N3), and the aromatic proton a (phenyl group of the initiator), good agreement was found between the feeding ratio and the actual ones in the polymer, as determined by the integration of the signals of interest in 1H NMR (Table S1). A similar observation was made for the case of PEG-CF-COOH as all the characteristic peaks of primary amide protons i′ (furfuryl), n′ (dopamine), u′ (PEG-N3), and the aromatic proton a′ (phenyl group of the initiator) can be visualized (Figure S2), and the ratio between their integration matches well with the designed ones (Table S1). It was determined that each polymer molecule contained six catechol and six furfuryl groups along with two PEG-COOH/-N3 chains, while the conversion of NSMA was quantitative. PEG-CF-N3 and PEG-CF-COOH polymer ligands bothcontains several furfuryl pendants and hold the capability to conjugate drug molecules bearing the maleimide group. The maleimide conjugation to the furfuryl ligand gives rise to a Diels–Alder adduct that can be cleaved by thermal energy.
To provide the proof of concept of click chemistry functionalization to the furfuryl group, fluorescein-derived maleimide (Fluo-Mal) and doxorubicin-derived maleimide (Doxo-Mal) were selected. Here, Doxo-Mal reacted with PEG-CF-N3, and the same chemistry was used to yield PEG-CDoxo-N3 by simply mixing PEG-CF-N3 with Doxo-Mal, followed by precipitation in diethyl ether. The reaction was carried out in DMF for 6 days at ambient temperature as this temperature is reported to promote the formation of more endo adducts than the exo one between the maleimido and the furfuryl moieties. (32) The polymer was purified by several dissolution–precipitation reactions in THF and diethyl ether, respectively. To avoid the risk of compromising the hydrophilicity of the resulting PEG-CDoxo-N3, a rather low amount of Doxo-Mal (10% molar equivalent with respect to the amount of furfuryl groups in the feeding polymer in the feeding ratio) was aimed. The 1H NMR spectrum of PEG-CDoxo-N3 is shown in Figure 1C in which the formation of the Diels–Alder adduct is evident (proton e′ and i′). The integration of i (from 8.50 to 8.25 ppm) and i′ (from 8.25 to 8.00 ppm) revealed a quantitative conjugation of Doxo-Mal to the polymer ligand platform.
On the other hand, Fluo-Mal was conjugated to PEG-CF-COOH to yield PEG-CFluo-COOH. The reaction and purification were done in the same way as shown for PEG-CDoxo-N3, except that the ratio of maleimide to furfuryl was fixed to be 25% as Fluo-Mal is less hydrophobic compared to Doxo-Mal. As shown in Figure 1D, all the characteristic peaks of fluorescein and the Diels–Alder adduct were detected in the 1H NMR spectrum of PEG-CFluo-COOH, and a quantitative conjugation was also verified. Thanks to its high selectivity, the dye/drug conjugation via the Diels–Alder reaction did not compromise the catechol functionalities as their characteristic peaks (Figure 1D,f,g,k,m) are preserved.
It is worthy to note that we also prepared the ligand polymer without introducing a longer functional PEG spacer to simplify the reaction procedure and make it more straightforward (Scheme S1). In this case, P(PEGMA-co-NSMA) was reacted with only a mixture of FA and DOPA.HCl to yield PEG-CF, as shown in the scheme in Figure S2A. The purification step was done in the same way as described above for the other two ligands, and the resulting PEG-CF was subjected to 1H NMR. The 1H NMR spectrum of PEG-CF shows the peaks of catechol pendants (Figure S3A, f,g,k,m) originated from dopamine pendants, and the characteristic signals of furfuryl moieties (Figure S3A, c, d, e) could also be assigned. In addition, the reduction of N-succinimidyl signal at 2.8 ppm along with the appearance of an amide proton (Figure S3A,n,i) verified successfully the reactions between P(PEGMA-co-NSMA) and the amino derivatives. Here, by comparing the integration of aromatic protons with the furfuryl (c, d, e), catechol (f, k, m), and phenyl group linking on the polymer of the initiator (a) (Figure S3A), it was determined that each polymer chain contained six catechol and eight furfuryl groups along with a quantitative conversion of NSMA. The conjugation of Fluo-Mal to PEG-CF to yield PEG-CFluo was also attempted using the same protocol developed for PEG-CFluo-COOH. Here, the ratio between Fluo-Mal to furfuryl was aimed at 66%. The solution after the reaction was washed thoroughly by five cycles of dissolution–precipitation in THF and diethyl ether subsequently. As demonstrated by the 1H NMR spectra (Figure S3B), no signal of free Fluo-Mal was detected in the spectrum of PEG-CFluo, while the signal of the Diels–Alder adduct (Figure S3B,e′) was clearly evident. In addition, the ratio between the integration of the Diels–Alder adduct peaks and catechol peaks indicated a quantitative conversion of Fluo-Mal.
The four synthesized ligands including PEG-CF, PEG-CFluo, PEG-CDoxo-N3, and PEG-CFluo-COOH were then used to phase transfer IONCs into water, initially capped with oleic acid, and dispersed in chloroform. For the synthesis of highly monodispersed IONCs, a solvothermal protocol previously reported by some authors was applied. (54) The chosen IONCs having a cube edge of 17 ± 2 nm were aimed as they have significant SAR values with heating losses that are less susceptible to the viscosity of the surrounding environment, that is, tumor and intracellular compartments, with respect to bigger nanocubes which may heat more, but their heat is significantly affected by viscosity. (55) In order to obtain single-coated IONCs, we have set a simple and scalable two-step phase transfer protocol, as shown in the scheme in Figure 2A. In the first step, IONCs were transferred from the organic phase into water using tetramethylammonium hydroxide (TMAOH), as reported elsewhere in the literature. (56) This step is aimed to exploit the electrostatic repulsion of ammonium cations absorbed on the IONCs surface to ensure proper dispersion of the nanocubes in water, the solvent used for the second ligand exchange step (Figure 2A).

Figure 2

Figure 2. Phase transfer of iron oxide nanocubes (IONCs) using a two-step ligand exchange. (A) Sketch represents the two-step phase transfer procedure involving first the transfer of IONCs from chloroform into water using tetramethylammonium hydroxide (TMAOH), followed by the postexchange in water of TMAOH with the developed ligands in basic solution, to yield physiologically stable IONCs. The dye/drug conjugated to the ligand platform via a thermal labile Diels–Alder adduct could be released by the local heat generated on the nanocube surface during MHT, as illustrated in the inset. FT-IR spectra of surface modification of IONCs for each step of the water transfer protocol (B) and in the extended region of interest from 1000 to 1900 cm–1 (C). Dynamic light scattering (DLS) traces of water-soluble IONCs modified with TMAOH (green), PEG-CF (blue), PEG-CFluo-COOH (red), and PEG-CDoxo-N3 (deep red) weighted by intensity (D). TEM images of IONCs functionalized with TMAOH (E), or with PEG-CF (F), or with PEG-CFluo-COOH (G), or with PEG-CDoxo-N3 (H) deposited from water.

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The phase transfer of IONCs from chloroform into water was carried out by dispersing IONCs in a TMAOH solution in ethanol which implies a ratio of 175 TMAOH ligands/nm2. Sonication at room temperature was used to assist the ligand exchange, followed by the addition of Milli-Q water and centrifugal filtration (see experimental section). This step was repeated twice to wash out the excess of TMAOH ligands. The nanoparticles were finally recovered and redispersed in Milli-Q water. Afterward, an aqueous solution of PEG-CF, used as a ligand model, (100 mg/mL of polymer), was added dropwise to this IONCs–TMAOH solution (12 gFe·L–1, 222 μL), followed by the Na2CO3 base addition (106 mg) to promote the ligand exchange. It is worth to mention that triethylamine (TEA) has been widely used as the base to promote the ligand exchange between catechol-based molecules and the iron oxide-rich surface. (19,48,51) However, TEA is a hazardous reagent as it is highly volatile with a pungent odor and toxic. (57) Here, taking advantage of the fact that the ligand exchange can be carried out in water, Na2CO3 was used as a mild and environment-friendly base to replace TEA. Having a similar pKa value (∼9.0), we expect a comparable performance between TEA and Na2CO3. Here, upon the addition of Na2CO3, the nanocubes solution turned milky. A drastic increase in the ionic strength of the solution might induce the flocculation of IONCs in this case.
Keeping the polymer IONCs solution for an overnight reaction under vigorous shaking, led to the phase separation between a black gel containing PEG-CF and IONCs-PEG-CF and Na2CO3 solution. This black gel was washed several times with water by magnetic decantation. Once the pH of the washed supernatant reached neutrality (ca. 7.0–7.4), this black gel was dispersed in neutral water, and the solution was left under shaking for 24 h until it became clear and homogeneous. The free PEG-CF and traces of Na2CO3 were removed by centrifugal filtration to yield a clear and stable solution of IONCs-PEG-CF. It is noticed that in a control experiment in which we used TEA instead of Na2CO3 as the base, it also allowed to obtain a stable and clear solution of IONCs-PEG-CF. In this case, TEA did not cause the formation of the gel, so no magnetic separation was needed, and the IONCs-PEG-CF were simply cleaned by centrifugal filtration after the ligand exchange. As a quick verification of the changes in the IONCs surface functionality, a proof of solubility in water was quickly preformed: by dissolving IONCs-TMAOH or IONCs-PEG-CF- (obtained either when using Na2CO3 or TEA as bases) in concentrated phosphate-buffered saline (PBS, 0.2 M), while the solution of IONCs–TMAOH in such media turned immediately cloudy and started the phase separation within the first few minutes, leading to sedimentation after 24 h (Figure S4), IONCs-PEG-CF in the same media remained stable without any phase separation even after 24 h. This indicates that the replacement of TMAOH on IONCs with PEG-CF took place and helped to stabilize the nanoparticles. We have also implemented the same procedure to transfer IONCs into water using PEG-CFluo, PEG-CFluo-COOH, and PEG-CDoxo-N3. Surprisingly, the IONCs functionalized with PEG-CFluo exhibited low water solubility with the formation of big floating particles even with intensive sonication. Apparently, the conjugation of a high dye amount (dye-to-furfuryl of 66%) makes the polymer ligand more hydrophobic, thus compromising its capability to solubilize IONCs in water. In contrast, PEG-CFluo-COOH and PEG-CDoxo-N3 successfully transfer IONCs into water, forming a stable ferrofluidic solution that remained stable during several cycles of centrifugal filtration. The free ligand was removed by means of ultracentrifugation using a sucrose gradient. Interestingly, IONCs-PEG-CFluo-COOH and IONCs-PEG-CDoxo-N3 exhibited stability in concentrated PBS buffer comparable to that of IONCs-PEG-CF (Figure S4). The obtained stable IONCs functionalized with different ligands were subjected to further dynamic light scattering (DLS) measurements. It is observed that initially we were using a PEG–CF ligand exchange procedure directly in chloroform (CHCl3), as the nanocubes and the polymer were fully soluble in this same solvent according to a previously reported protocol applied for other similar polymers. (53) In doing so, PEG-CF and IONCs were mixed in CHCl3 at a catechol/nm2 ratio of 25 along with an excess amount of triethylamine (500 TEA/nm2) and left to react for an overnight period. Afterward, an excess amount of hexane was added to induce the precipitation of particles. Upon centrifugation, the supernatant was discarded, and the resulting black pellet was dried under nitrogen flow, followed by water addition. The free ligand was removed by centrifugal filtration. Although the IONCs upon ligand exchange can be readily dispersed in water, TEM revealed a predominant presence of small clusters of IONCs together with individually coated nanocubes (Figure S5A,B). This observation is in good agreement with DLS measurements in which the IONCs showed a high hydrodynamic size (dH) of ∼200 nm weighted by intensity (Figure S5C). This might be due to a strong magnetic interaction between IONCs as they have the magnetic core size and distribution at the edge between superparamagnetic and ferromagnetic. (14,38) As reported in our previous studies, such clustering may compromise the MHT heating capability of IONCs either in solution or in viscous media; (41) moreover, having a large dH implies that these clusters are likely to be less desirable for systemic delivery. We therefore chose the two-step approach with the intermediate solubilization in water via TMAOH for a better final water-soluble product.
The evolution of IONCs’ surface functionality was further confirmed by the FT-IR fingerprint of the same nanocube at each of the functionalization steps. The FT-IR spectra of oleic acid-capped pristine IONCs show the absorption bands of the stretching vibrations of alkyl (3000–2800 cm–1), carbonyl (1710 cm–1), and carboxylate (1490 cm–1) groups, indicating the presence of oleic acid as the surface ligand (Figure 2B,C, black curve). Upon the phase transfer using TMAOH, the characteristic absorption bands of hydroxyl (−OH) and C–N at 3300 and 1600 cm–1, respectively, can be clearly identified (green curve). The FT-IR spectra of IONCs-PEG-CF (blue curve) show the appearance of distinguished signals of carbonyl stretching at 1720 cm–1 (ester) and 1652 cm–1 (amide), along with the strong and characteristic bands of the ether bond (C–O–C) at 1100 cm–1 which confirm the existence of PEG-CF on the surface of IONCs. A similar observation was made for IONCs-PEG-CFluo-COOH and PEG-CDoxo-N3. Here, FT-IR measurements (Figure 2B,C) confirmed the existence of PEG-CFluo-COOH (red curve) and PEG-CDoxo-N3 (deep red curve) on the surface of IONCs upon the modification step, as the characteristic absorption bands of carbonyl (C═O, ester, and amide) and ether (C–O–C) can be clearly assigned to 1722, 1656, and 1105 cm–1, respectively. In the case of IONCs-PEG-CDoxo-N3 (Figure 2B, inset), a characteristic absorption band of azide group at 2150 cm–1 can also be detected, confirming the presence of PEG-CDoxo-N3 on the surface of IONCs.
The colloidal properties of IONCs during the surface modification steps were monitored by means of DLS. dH weighted by intensity, volume, and number along with the polydispersity index (PDI) for each sample is reported in Table 1. As shown in Figure 2D, the DLS traces of IONCs transferred in water using TMAOH showed a single peak along with a small hydrodynamic diameter (dH) of 48 ± 20 nm (the maximum peak value weighted by intensity with the half width at half-maximum) and a low PDI of 0.12 with no sign of aggregation (black curve). Even the dH weighted by volume (35 ± 14 nm) and number (27 ± 8 nm) further verified that TMAOH-IONCs were present as a single entity in water solution (Figure S6A,B). Interestingly, the replacement of TMAOH with PEG-CF on the IONCs’ surface (using Na2CO3 as the base) led to an increase of their dH to 87 ± 42 nm (weighted by intensity) without any traces of aggregation, while the PDI remains as low as 0.20 (Figure 2D, red curve). The corresponding dH values weighted by number and volume are also consistent with the one weighted by intensity (Table 1 and Figure S6A,B). On the other hand, dH (weighted by intensity) of IONCs-PEG-CDoxo-N3 showed the main peak at 41 ± 16 nm (PDI ∼ 0.29), indicating an individual coating of IONCs in solution (Figures 2D and S6A,B) for the DLS traces weighted by volume and number. For IONCs-PEG-CFluo-COOH, the DLS data revealed a dH value of 76 ± 33 nm (weighted by intensity) along with a PDI of 0.29, also supported by the same monomodal traces of dH values weighted by number and volume (Figures 2D, S6 and Table 1), thus verifying the good colloidal stability. Interestingly, IONCs capped with PEG-CFluo-COOH also exhibit good stability in PBS (50 mM, pH 7.4), as demonstrated by DLS measurements. As shown in Figure S7A, dH (weighted by intensity) of PEG-CFluo-COOH in PBS was found to be as small as 61 ± 36 nm (PDI 0.18) and remained unchanged after 21 days of storage on bench under ambient conditions (Figure S7B) as well as the DLS traces weighted by number and volume (Figure S7). It is observed that even for the IONCs-CF-N3 and IONCs-PEG-CDoxo-N3 samples, the nanocubes before and after Doxo functionalization were both stable in PBS, as confirmed by the monomodal DLS traces (Figure S7C). The data from DLS are in good agreement with those of TEM. As can be seen in Figure 2E–H, IONCs functionalized with TMAOH (deposited from water) are well dispersed on the TEM grid with a few grouping of nanocubes likely due to the drying effect (Figure 2E). The same observation was made in the case of IONCs-PEG-CF, IONCs-PEG-CFluo-COOH, and IONCs-PEG-CDoxo-N3 as IONCs form a monolayer of nanoparticles and no apparent signs of aggregation were detected (Figure 2F–H).
Table 1. Hydrodynamic Size (dH) of IONCs Modified with TMAOH, PEG-CF, PEG-CFluo-COOH, and PEG-CDoxo-N3 Weighted by Intensity, Volume, and Number along with PDI Values
sampledH intensity-weighted (nm)dH volume-weighted (nm)dH number-weighted (nm)PDI
IONCs-TMAOH48 ± 2035 ± 1427 ± 80.12
IONCs-PEG-CF87 ± 4247 ± 2828 ± 110.20
IONCs-PEG-CFluo-COOH76 ± 3348 ± 2334 ± 110.29
IONCs-PEG-CDoxo-N341 ± 1628 ± 1022 ± 60.29
Aiming at applying this platform to tumor cells, the stability of IONCs functionalized with PEG-CDoxo-N3 was investigated. In this experiment, surface-modified IONCs were dissolved in DMEM tumor cell culture media at 10% fetal bovine serum (FBS) at [Fe] ∼ 0.1 g/L. The stability of IONCs-PEG-CDoxo-N3 in such a solution was monitored at room temperature by visual inspection and DLS characterization at days 0, 2, 5, and 8 days (Figure 3A). The DLS traces (weighted by intensity) of IONCs-PEG-CF-N3 at day 0 revealed a bimodal size distribution. The small peak at 9 ± 3 nm might be due to the existence of serum protein in solution, while the peak at 51 ± 27 nm is compatible with our IONCs. The increase in IONCs-PEG-CDoxo-N3 could be attributed to the formation of protein corona on the NP surface. At 8 days of incubation, the dH value of IONCs-PEG-CDoxo-N3 increased gradually up to 77 ± 35 nm. This could be explained by the increase of protein corona or slow clustering of IONCs. However, a dH value below 100 nm is still suitable for efficient accumulation at the solid tumor. Notably, even after 8 days, no signs of sedimentation are observed, and the IONC solution still appeared homogeneous (Figure 3A, inset). We also performed the same stability experiment for IONCs functionalized with PEG-CF-N3. Also in this case, similar observations were made as the dH value of IONCs-PEG-CF-N3 in 10% FBS remained below 100 nm (Figure 3B), and no visual precipitates (Figure 3B, inset) were detected in solution up to 8 days of incubation. As such, the conjugation of Doxo-Mal resulted in a negligible impact on the capability of PEG-CF-N3 to stabilize IONCs in media.

Figure 3

Figure 3. Stability of IONCs functionalized with multidentate and functional polymer ligands in physiological conditions. DLS traces of IONCs modified with PEG-CDoxo-N3 (A) or with PEG-CF-N3 (B) dispersed in complete cell culture media at 10% fetal bovine serum at day 0 and after 2, 5, and 8 days of storage at ambient conditions. The insets show the vials, as observed under visible light for the culture media (1) and for IONCs modified with either PEG-CDoxo-N3 or PEG-CF-N3 ligands, respectively (2).

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Thanks to the high colloidal stability, IONCs capped with TMAOH and PEG-CF showed SAR values above 350 W·g–1, measured using the calorimetric method under MHT conditions (24 kA·m–1 and 180 kHz) and below the biological limit (H·f < 5 × 109 A·m–1·s–1). Here, IONCs–TMAOH shows an outstanding SAR value of 460 W·g–1 (Figure 4A), while changing the surface ligand to PEG-CF led to a slight drop of SAR by 20%, regardless of the use of organic (TEA) or inorganic base (Na2CO3). Owing to its good stability, IONC-PEG-CFluo-COOH also shows a SAR value as high as 420 W·g–1 (Figure 4A) when being exposed to an MHT with respect to the biological limit (24 kA·m–1, 180 kHz). This SAR value was found to be slightly lower than that of IONC–TMAOH (drop by 10%) but higher than the value measured for IONC-PEG-CF (360 W·g–1). We next investigated the SAR value of IONC-PEG-CFluo-COOH in viscous media (Figure 4B). Indeed, as the viscosity in tumor and intracellular compartments is far higher than that in water, the evaluation of the heating capability in viscous media is an important criterion to realize the actual potential of the heat transducer in MHT. (41,55,58) The SAR measurements on IONC-PEG-CFluo-COOH were therefore performed in water and in glycerol solution (81%) at the same Fe concentration (3.5 g/L). Here, a clinically used frequency of 110 kHz was aimed while the field amplitude was varied from 16 to 40 kA·m–1 to ensure that the H·f factor was always below 5 × 109 A·m–1·s–1. Notably, we found that SAR of IONC-PEG-CFluo-COOH in water increased linearly as a function of field amplitude in the range from 16 to 32 kA·m–1, while there was no significant difference between the SAR values measured at 32 and 40 kA·m–1 (Figure 4B). A similar trend was obtained for the same IONC-PEG-CFluo-COOH dispersed in 81% glycerol solution, and the SAR value of IONC-PEG-CFluo-COOH in glycerol solution did not decrease when the viscosity of the media was increased from 1.0 to 91.0 mPa·s (Figure 4B). Here, drops by 15–35% were observed depending on the field of the measurement. Apparently, the intermediate field amplitudes (24 and 32 kA·m–1) resulted in a less dependence of heating capacity of IONCs-PEG-CFluo-COOH on the media viscosity. This could be due to some alignments of IONCs in high viscous media in these field conditions that enhance their heating performance. (59) SAR values measured under other MHT conditions (24 kA·m–1 and 180 kHz) in viscous media also showed only a marginal drop by 18% (Figure 4C). It is worthy to mention that IONCs functionalized with PEG-CFluo-COOH in our study have among the highest SAR value reported for iron oxide-based nanoparticles (having a similar lateral size for nanocubes or magnetic volume for spherical nanoparticles) in such highly viscous media. (41,58,60) Although detailed investigations on SAR of IONCs-PEG-CDoxo-N3 were not conducted in our current study, we believe that the heating performance of such IONCs is comparable to IONC-PEG-CFluo-COOH as these two samples have the same edge sizes and exhibit a similar colloidal stability, represented by comparable dH. As such, IONCs functionalized with either PEG-CFluo-COOH or PEG-CDoxo-N3 represent promising candidates for practical MHT against solid tumor (Figure 4).

Figure 4

Figure 4. Heating capability of IONCs in water and viscous media. (A) Specific absorption rate (SAR) values in water of IONCs having different surface ligands. (B,C) Comparison of the SAR value of IONCs functionalized with PEG-CFluo-COOH in water and viscous media (glycerol 81%) measured under the MHT conditions with respect to the biological limit (H·f < 5 × 109 A·m–1·s–1). The values reported in panel 4B were measured at 110 kHz, with the field varied from 16 to 40 kA·m–1.

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We next used IONCs-PEG-CDoxo-N3 and IONCs-PEG-CFluo-COOH as models to study the release of active molecules linked to IONCs via the thermal labile Diels–Alder adduct. The temperature at the surface of IONCs during MHT is far higher than the one in solution; (18,19) thus, the ability to inducing the retro-Diels-Alder reaction (the breakage) to achieve the release without the need of heating the whole solution was aimed. In the first set of experiments, IONCs-PEG-CDoxo-N3 was used. Given the very low solubility of Doxo-Mal in water, this experiment was carried out in H2O/DMF (50% in volume) as the release media. To attest the percentage of Doxo loaded, the IONCs-PEG-CDoxo-N3 solution was immersed in a water bath set at 70 °C. At this temperature, the cleavage of the endo adduct occurs, being this temperature above 60 °C. The supernatant, after the treatment, was separated by means of centrifugation at a high speed, followed by one cycle of magnetic decantation. An attempt to use centrifugal filtration to separate the supernatant was not successful as Doxo was found to be stuck to the filtering membrane (data not shown). The final supernatant was subjected to photoluminescence (PL) measurement. Here, we noticed that the amount of PL signal of the supernatant remained the same between 4 and 7 h of water bath treatment, indicating a complete thermal cleaving of the endo adduct. After subtracting the PL signal from the non-specific release, a loading capacity of 46 μg Doxo per 1 mgFe was determined using the calibration of Doxo–Mal in the same media (Figure S8). It is important to note that the actual loaded amount of Doxo will be higher; however, we only considered the one that can be cleaved via mild thermal treatment in this loading capacity determination. We next investigated the release carried out at [Fe] as low as 0.5 g/L with and without MHT exposure. Here, we used an identical MHT condition that has been used in clinic (16 kA·m–1 and 110 kHz). The sample was exposed to such MHT condition for different periods (from 10 to 90 min) As shown in Figure 5A (orange curve), the temperature rise in this MHT condition was negligible with an increment of less than 1.0 °C (solution temperature reached 21 °C, and the temperature remained unchanged in the control experiment without IONCs). The amount of released Doxo was measured by the photoluminescence (PL) intensity of collected supernatants (excitation of 475 nm and emission of 593 nm). The PL of the sample exposed to MHT is evidently higher than that of the one kept at room conditions (Figure 5B). The non-specific release in the case of samples kept at room temperature and not exposed to MHT might be due to a small amount of leaching ligands during the centrifugation step used to separate the free Doxo from the nanocube fraction. (19,22) Similar observations were made when comparing the release at different time periods. The PL intensity of the sample exposed to 90 min of MHT is 50% higher than that of the non-treated one (Figure 5C). The same trend of release was obtained when a solution having higher Fe concentration was used (1.0 g/L) (Figure S9A). In this case, the solution temperature increased by 3 °C, reaching 23 °C (Figure 5A, red curve) during the MHT treatment. Here, 11.3 and 7.1% of loaded Doxo were released after 90 min of MHT at [Fe] of 0.5 and 1.0 g/L, respectively. More importantly, we found that the normalized concentration of Doxo released (calculated by excluding the PL contribution from the nonspecific release) even at low Fe concentration used (0.5 g/L) after 10–90 min of MHT is in the range from 1.3 to 3.6 μM (Figure 5C). The concentration of released drug was determined using a calibration curve of Doxo–Mal in H2O:DMF (50% volume) (Figure S8). When a solution having higher Fe concentration was used, the concentration of Doxo released falls in the range between 1.9 and 4.5 μM (Figure 5C).

Figure 5

Figure 5. Release of dye molecules by means of MHT-induced local (hot-spot) heat effect. Heating profiles of IONC-PEG-CDoxo-N3 (A) and IONC-PEG-CFluo-COOH (D) solution in water at different Fe concentrations (0.5 and 1.0 g/L) and control solution (only water) under MHT (16 kA·m–1 and 110 kHz) during the first 10 min of MHT. We observed that the maximum temperature was reached after 10 min; thus, further heating profiles are not shown. The comparison of the PL signal of Doxo (B) and fluorescein sodium salt (E) between the samples kept on bench and the one undergoing MHT (110 kHz, 16 kA·m–1) at the Fe concentration of 0.5 gFe/L (at different durations of MHT). The normalized concentration of Doxo (C) and fluorescein sodium salt (F) released upon MHT (16 kA·m–1 and 110 kHz) at Fe concentrations of 0.5 gFe/L.

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Next, the release experiment was performed on IONC-PEG-CFuo-COOH. Compared to the experiment with IONC-CDoxo-N3, a similar increase of temperature was obtained in this case during the MHT at [Fe] of 0.5 and 1.0 g/L (Figure 5D). Thanks to the better solubility of the cleaved fluorescein sodium salt, the supernatant after MHT could be separated by centrifugal filtration as the released dyes could pass through the filtering membrane easily. As expected, the amount of dyes released for the sample undergoing MHT at 10, 20, and 30 min is always higher than the one left on bench. After 30 min of MHT, the photoluminescence signals of MHT-treated samples are almost double in comparison to the one of the nontreated one for [Fe] of 0.5 and 1.0 g/L (Figures 5E and S9B). Interestingly, we found that the signal from the nonspecific release was much less with respect to the case of IONC-PEG-CDoxo-N3. Such difference might be due to the difference in the centrifugal speed used to precipitate out the nanocubes from the solution. Indeed, due to the very high colloidal stability of IONC-PEG-CDoxo-N3 in water, a very high spinning speed (14,500 rpm) was needed to sediment the nanocubes, leading to a more shear-thinning force. This, in turn, will induce more ligand leaching from the IONC surface. Nevertheless, the normalized concentration of dyes released at [Fe] of 0.5 g/L after 10 to 30 min of MHT is in the range from 1.0 to 4.0 μM (Figure 5F) using a calibration curve of fluorescein sodium salt in water (Figure S10). When a solution having a higher dose of nanocubes was used (1.0 g/L in iron), higher amounts of dyes were released in the range between 0.9 and 5.1 μM (Figure 5F).
Notably, these μM concentration ranges in the case of either Doxo or fluorescein release are in the therapeutic window of most antitumor chemotherapies that have been used to treat cancer. (22,24,25,61) As such, our developed drug ligand IONC platform may enable the release of sufficient amount of drug by means of magnetic induction for clinical use and at a nanoparticle dose quite low as never achieved before.

Conclusions

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We have disclosed a novel polydentate and multifunctional polymer ligand for the preparation of highly stable iron oxide nanocubes (IONCs) in physiological conditions. We took advantage of the high reactivity of poly(polyethylene glycol methacrylate-co-N-succinimidyl methacrylate) toward primary amines to prepare well-defined polymer ligands having several azide- and carboxylic acid-functionalized polyethylene glycol chains, catechol, and furfuryl pendants. Multiple catechol anchors provide a strong binding of this ligand platform to the iron oxide nanocube surface, while functional PEG chains ensure an excellent stability of IONCs in buffer saline solution or enable to control the hydrophilicity of the polymer ligand molecule, along with the possibility to post-functionalize with the desired biomolecules. Indeed, the furfuryl side groups enable the conjugation of molecule of interest (here, a dye molecule and doxorubicin as drug model systems) via a thermal labile Diels–Alder adduct. A two-step post-ligand exchange procedure was used for water transfer of IONCs. IONCs transferred in water using the developed ligand platform show outstanding SAR values as high as 420 W·g–1 when being exposed to an alternating magnetic field of biological limit. It is remarkable that SARs of IONCs capped with a polymer ligand dropped by only 15–30% when the measurements were performed on the sample dispersed in viscous media (91 mPa·s). Most importantly, the release of conjugated dyes/drugs can be triggered by exposing IONCs to MHT condition applied in the clinic (16 kA·m–1, 110 kHz) when measuring a change in temperature of only few degrees. Peculiarly, at a nanocube concentration as low as 0.5 or 1 g/L of iron corresponding to the dose of nanocubes of as low as 0.05 or 0.1 mg (considering a tumor volume of 100 mm3 in the in vivo model), the amount of released dyes/drugs from nanocubes under MHT was in the dose range 1.0–5.0 μM, being in line with the therapeutic range of various chemotherapies used for cancer treatment. This platform is especially appealing in the case of systemic injection of MNPs when the accumulation dose at the tumor often is not enough to guarantee the macroscopic temperature elevation for drug release. The AMF in clinical conditions could be used, indeed, as the remote actuator for the drug release activation. In addition, the versatility of this established polymer ligand platform can be further exploited to link different functional molecules via Diels–Alder click chemistry, thus enabling the exploration of the new applications of IONCs for mild MHT-activated anticancer therapies.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsami.2c14752.

  • Description of materials, synthesis, 1H NMR of polymer ligand, TEM images and DLS traces of IONCs, and release profile of dye/drug with and without MHT activation (PDF)

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Author Information

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  • Corresponding Authors
  • Authors
    • John S. Conteh - Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy
    • Helena Gavilán - Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy;  Present Address: Departamento de Ciencia e Ingeniería de Materiales e Ingeniería Química, IAAB, Universidad Carlos III de Madrid, Avda. de la Universidad, 30, 28911 Leganés, Madrid, Spain (H.G.)
    • Alessandro Di Girolamo - Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This work was partially supported by the Marie Skłodowska-Curie Innovative training network MSCA-ITN-ETN (HeatNMof project, GA 860942), partially by the AIRC Foundation (AIRC IG-14527 to T.P.), partially by the European Research Council (starting grant ICARO, Contract No. 678109), and partially by ERC proof of concept Hypercube, Contract No. 899661).

References

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    A review. The combination of hard matter, like magnetic nanoparticles (MNPs) and soft materials, like polymers, can generate multi-purpose materials with a broad range of applications. Here, the merging of unique features of MNPs with peculiar polymer responsiveness properties, such as pH and thermo-stimuli activation, enable the smart control of polymer properties operated by the magnetic nanoparticles and vice versa, at a level of unprecedented sophistication. These magnetic-stimuli-responsive nanosystems have impacted the medical research with evidences for controlled drug delivery and for tracking the drug release; for combining magnetic hyperthermia and stimuli-dependent drug delivery, and for diagnosis pathol. conditions (such as pH-changes at ischemic site). Despite great efforts by chemists to fabricate different featured materials, proof of concepts are widely demonstrated in vitro in test tubes and in cell studies but successfully preclin. studies are only few. A clin. translation of magnetic stimuli-responsive systems would require overcoming the actual nanosystem limitations and the joint efforts of an interdisciplinary scientific community. By framing state of the art of magnetic-stimuli-responsive systems following an organization based on the response mechanisms of polymers, challenges to overcome and future directions are suggested in this perspective.
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  5. 5
    Cardoso, V. F.; Francesko, A.; Ribeiro, C.; Bañobre-López, M.; Martins, P.; Lanceros-Mendez, S. Advances in Magnetic Nanoparticles for Biomedical Applications. Adv. Healthcare Mater. 2018, 7, 1700845  DOI: 10.1002/adhm.201700845
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    Chang, D.; Lim, M.; Goos, J. A.; Qiao, R.; Ng, Y. Y.; Mansfeld, F. M.; Jackson, M.; Davis, T. P.; Kavallaris, M. Biologically Targeted Magnetic Hyperthermia: Potential and Limitations. Front. Pharmacol. 2018, 9, 831,  DOI: 10.3389/fphar.2018.00831
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    Biologically targeted magnetic hyperthermia: potential and limitations
    Chang, David; Lim, May; Goos, Jeroen A. C. M.; Qiao, Ruirui; Ng, Yun Yee; Mansfeld, Friederike M.; Jackson, Michael; Davis, Thomas P.; Kavallaris, Maria
    Frontiers in Pharmacology (2018), 9 (), 831/1-831/20CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)
    Hyperthermia, the mild elevation of temp. to 40-43°C, can induce cancer cell death and enhance the effects of radiotherapy and chemotherapy. However, achievement of its full potential as a clin. relevant treatment modality has been restricted by its inability to effectively and preferentially heat malignant cells. The limited spatial resoln. may be circumvented by the i.v. administration of cancer-targeting magnetic nanoparticles that accumulate in the tumor, followed by the application of an alternating magnetic field to raise the temp. of the nanoparticles located in the tumor tissue. This targeted approach enables preferential heating of malignant cancer cells while sparing the surrounding normal tissue, potentially improving the effectiveness and safety of hyperthermia. Despite promising results in preclin. studies, there are numerous challenges that must be addressed before this technique can progress to the clinic. This review discusses these challenges and highlights the current understanding of targeted magnetic hyperthermia.
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  7. 7
    Chandrasekharan, P.; Tay, Z. W.; Hensley, D.; Zhou, X. Y.; Fung, B. K.; Colson, C.; Lu, Y.; Fellows, B. D.; Huynh, Q.; Saayujya, C.; Yu, E.; Orendorff, R.; Zheng, B.; Goodwill, P.; Rinaldi, C.; Conolly, S. Using Magnetic Particle Imaging Systems to Localize and Guide Magnetic Hyperthermia Treatment: Tracers, Hardware, and Future Medical Applications. Theranostics 2020, 10, 2965,  DOI: 10.7150/thno.40858
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    7
    Using magnetic particle imaging systems to localize and guide magnetic hyperthermia treatment: tracers, hardware, and future medical applications
    Chandrasekharan, Prashant; Tay, Zhi Wei; Hensley, Daniel; Zhou, Xinyi Y.; Fung, Barry K. L.; Colson, Caylin; Lu, Yao; Fellows, Benjamin D.; Huynh, Quincy; Saayujya, Chinmoy; Yu, Elaine; Orendorff, Ryan; Zheng, Bo; Goodwill, Patrick; Rinaldi, Carlos; Conolly, Steven
    Theranostics (2020), 10 (7), 2965-2981CODEN: THERDS; ISSN:1838-7640. (Ivyspring International Publisher)
    A review. Magnetic fluid hyperthermia (MFH) treatment makes use of a suspension of superparamagnetic iron oxide nanoparticles, administered systemically or locally, in combination with an externally applied alternating magnetic field, to ablate target tissue by generating heat through a process called induction. The heat generated above the mammalian euthermic temp. of 37°C induces apoptotic cell death and/or enhances the susceptibility of the target tissue to other therapies such as radiation and chemotherapy. While most hyperthermia techniques currently in development are targeted towards cancer treatment, hyperthermia is also used to treat restenosis, to remove plaques, to ablate nerves and to alleviate pain by increasing regional blood flow. While RF hyperthermia can be directed invasively towards the site of treatment, non-invasive localization of heat through induction is challenging. In this review, we discuss recent progress in the field of RF magnetic fluid hyperthermia and introduce a new diagnostic imaging modality called magnetic particle imaging that allows for a focused theranostic approach encompassing treatment planning, treatment monitoring and spatially localized inductive heating.
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  8. 8
    Gavilán, H.; Avugadda, S. K.; Fernández-Cabada, T.; Soni, N.; Cassani, M.; Mai, B. T.; Chantrell, R.; Pellegrino, T. Magnetic Nanoparticles and Clusters for Magnetic Hyperthermia: Optimizing Their Heat Performance and Developing Combinatorial Therapies to Tackle Cancer. Chem. Soc. Rev. 2021, 50, 11614– 11667,  DOI: 10.1039/D1CS00427A
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    8
    Magnetic nanoparticles and clusters for magnetic hyperthermia: optimizing their heat performance and developing combinatorial therapies to tackle cancer
    Gavilan, Helena; Avugadda, Sahitya Kumar; Fernandez-Cabada, Tamara; Soni, Nisarg; Cassani, Marco; Mai, Binh T.; Chantrell, Roy; Pellegrino, Teresa
    Chemical Society Reviews (2021), 50 (20), 11614-11667CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    A review. Magnetic hyperthermia (MHT) is a therapeutic modality for the treatment of solid tumors that has now accumulated more than 30 years of experience. In the ongoing MHT clin. trials for the treatment of brain and prostate tumors, iron oxide nanoparticles are employed as intra-tumoral MHT agents under a patient-safe 100 kHz alternating magnetic field (AMF) applicator. Although iron oxide nanoparticles are currently approved by FDA for imaging purposes and for the treatment of anemia, magnetic nanoparticles (MNPs) designed for the efficient treatment of MHT must respond to specific phys.-chem. properties in terms of magneto-energy conversion, heat dose prodn., surface chem. and aggregation state. Accordingly, in the past few decades, these requirements have boosted the development of a new generation of MNPs specifically aimed for MHT. In this review, we present an overview on MNPs and their assemblies produced via different synthetic routes, focusing on which MNP features have allowed unprecedented heating efficiency levels to be achieved in MHT and highlighting nanoplatforms that prevent magnetic heat loss in the intracellular environment. Moreover, we review the advances on MNP-based nanoplatforms that embrace the concept of multimodal therapy, which aims to combine MHT with chemotherapy, radiotherapy, immunotherapy, photodynamic or phototherapy. Next, for a better control of the therapeutic temp. at the tumor, we focus on the studies that have optimized MNPs to maintain gold-std. MHT performance and are also tackling MNP imaging with the aim to quant. assess the amt. of nanoparticles accumulated at the tumor site and regulate the MHT field conditions. To conclude, future perspectives with guidance on how to advance MHT therapy will be provided.
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  9. 9
    Cazares-Cortes, E.; Cabana, S.; Boitard, C.; Nehlig, E.; Griffete, N.; Fresnais, J.; Wilhelm, C.; Abou-Hassan, A.; Ménager, C. Recent Insights in Magnetic Hyperthermia: From the “Hot-Spot” Effect for Local Delivery to Combined Magneto-Photo-Thermia Using Magneto-Plasmonic Hybrids. Adv. Drug Delivery Rev. 2019, 138, 233– 246,  DOI: 10.1016/j.addr.2018.10.016
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    9
    Recent insights in magnetic hyperthermia: From the "hot-spot" effect for local delivery to combined magneto-photo-thermia using magneto-plasmonic hybrids
    Cazares-Cortes, Esther; Cabana, Sonia; Boitard, Charlotte; Nehlig, Emilie; Griffete, Nebewia; Fresnais, Jerome; Wilhelm, Claire; Abou-Hassan, Ali; Menager, Christine
    Advanced Drug Delivery Reviews (2019), 138 (), 233-246CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)
    A review. Magnetic hyperthermia which exploits the heat generated by magnetic nanoparticles (MNPs) when exposed to an alternative magnetic field (AMF) is now in clin. trials for the treatment of cancers. However, this thermal therapy requires a high amt. of MNPs in the tumor to be efficient. On the contrary the hot spot local effect refers to the use of specific temp. profile at the vicinity of nanoparticles for heating with minor to no long-range effect. This magneto-thermal effect can be exploited as a relevant external stimulus to temporally and spatially trigger drug release. In this review, we focus on recent advances in magnetic hyperthermia. Indirect exptl. proofs of the local temp. increase are first discussed leading to a good estn. of the temp. at the surface (from 0.5 to 6 nm) of superparamagnetic NPs. Then we highlight recent studies illustrating the hot-spot effect for drug-release. Finally, we present another recent strategy to enhance the efficacity of thermal treatment by combining photothermal therapy with magnetic hyperthermia mediated by magneto-plasmonic nanoplatforms.
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  10. 10
    Mahmoudi, K.; Bouras, A.; Bozec, D.; Ivkov, R.; Hadjipanayis, C. Magnetic Hyperthermia Therapy for the Treatment of Glioblastoma: A Review of the Therapy’s History, Efficacy and Application in Humans. Int. J. Hyperthermia 2018, 34, 1316– 1328,  DOI: 10.1080/02656736.2018.1430867
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    10
    Magnetic hyperthermia therapy for the treatment of glioblastoma: a review of the therapy's history, efficacy and application in humans
    Mahmoudi Keon; Bouras Alexandros; Bozec Dominique; Hadjipanayis Constantinos; Ivkov Robert; Hadjipanayis Constantinos
    International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group (2018), 34 (8), 1316-1328 ISSN:.
    Hyperthermia therapy (HT) is the exposure of a region of the body to elevated temperatures to achieve a therapeutic effect. HT anticancer properties and its potential as a cancer treatment have been studied for decades. Techniques used to achieve a localised hyperthermic effect include radiofrequency, ultrasound, microwave, laser and magnetic nanoparticles (MNPs). The use of MNPs for therapeutic hyperthermia generation is known as magnetic hyperthermia therapy (MHT) and was first attempted as a cancer therapy in 1957. However, despite more recent advancements, MHT has still not become part of the standard of care for cancer treatment. Certain challenges, such as accurate thermometry within the tumour mass and precise tumour heating, preclude its widespread application as a treatment modality for cancer. MHT is especially attractive for the treatment of glioblastoma (GBM), the most common and aggressive primary brain cancer in adults, which has no cure. In this review, the application of MHT as a therapeutic modality for GBM will be discussed. Its therapeutic efficacy, technical details, and major experimental and clinical findings will be reviewed and analysed. Finally, current limitations, areas of improvement, and future directions will be discussed in depth.
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  11. 11
    Southern, P.; Pankhurst, Q. A. Commentary on the Clinical and Preclinical Dosage Limits of Interstitially Administered Magnetic Fluids for Therapeutic Hyperthermia Based on Current Practice and Efficacy Models. Int. J. Hyperthermia 2018, 34, 671– 686,  DOI: 10.1080/02656736.2017.1365953
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    11
    Commentary on the clinical and preclinical dosage limits of interstitially administered magnetic fluids for therapeutic hyperthermia based on current practice and efficacy models
    Southern, Paul; Pankhurst, Quentin A.
    International Journal of Hyperthermia (2018), 34 (6), 671-686CODEN: IJHYEQ; ISSN:0265-6736. (Taylor & Francis Ltd.)
    We offer a critique of what constitutes a suitable dosage limit, in both clin. and preclin. studies, for interstitially administered magnetic nanoparticles in order to enable therapeutic hyperthermia under the action of an externally applied alternating magnetic field. We approach this first from the perspective of the currently approved clin. dosages of magnetic nanoparticles in the fields of MRI contrast enhancement, sentinel node detection, iron replacement therapy and magnetic thermoablation. We compare this to a simple anal. model of the achievable hyperthermia temp. rise in both humans and animals based on the interstitially administered dose, the heating and dispersion characteristics of the injected fluid, and the strength and frequency of the applied magnetic field. We show that under appropriately chosen conditions a therapeutic temp. rise is achievable in clin. relevant situations. We also show that in such cases it may paradoxically be harder to achieve the same therapeutic temp. rise in a preclin. model. We comment on the implications for the evidence-based translation of hyperthermia based interventions from the lab. to the clinic.
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  12. 12
    Attaluri, A.; Kandala, S. K.; Zhou, H.; Wabler, M.; DeWeese, T. L.; Ivkov, R. Magnetic Nanoparticle Hyperthermia for Treating Locally Advanced Unresectable and Borderline Resectable Pancreatic Cancers: The Role of Tumor Size and Eddy-Current Heating. Int. J. Hyperthermia 2020, 37, 108– 119,  DOI: 10.1080/02656736.2020.1798514
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    12
    Magnetic nanoparticle hyperthermia for treating locally advanced unresectable and borderline resectable pancreatic cancers: the role of tumor size and eddy-current heating
    Attaluri, Anilchandra; Kandala, Sri Kamal; Zhou, Haoming; Wabler, Michele; DeWeese, Theodore L.; Ivkov, Robert
    International Journal of Hyperthermia (2020), 37 (3), 108-119CODEN: IJHYEQ; ISSN:0265-6736. (Taylor & Francis Ltd.)
    Tumor vol. largely dets. the success of local control of borderline resectable and locally advanced pancreatic cancer with current therapy. We hypothesized that a tumor-mass normalized dose of magnetic nanoparticle hyperthermia (MNPH) with alternating magnetic fields (AMFs) reduces the effect of tumor vol. for treatment. 18 female athymic nude mice bearing s.c. MiaPaCa02 human xenograft tumors were treated with MNPH following intratumor injections of 5.5 mg Fe/g tumor of an aq. suspension of magnetic iron-oxide nanoparticles. Mice were randomly divided into control (n = 5) and treated groups having small (0.15 ± 0.03 cm3, n = 4) or large (0.30 ± 0.06 cm3, n = 5) tumors. We assessed the clin. feasibility of this approach and of pulsed AMF to minimize eddy current heating using a finite-element method to solve a bioheat equation for a human-scale multilayer model. Compared to the control group, both small and large MiaPaCa02 s.c. tumors showed statistically significant growth inhibition. Conversely, there was no significant difference in tumor growth between large and small tumors. Both computational and xenograft models demonstrated higher max. tumor temps. for large tumors compared to small tumors. Computational modeling demonstrates that pulsed AMF can minimize nonspecific eddy current heating. MNPH provides an advantage to treat large tumors because the MION dose can be adjusted to increase power. Pulsed AMF, with adjusted treatment time, can enhance MNPH in challenging cases such as low MION dose in the target tissue and/or large patients by minimizing nonspecific eddy current heating without sacrificing thermal dose to the target. Nanoparticle heterogeneity in tumors remains a challenge for continued research.
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    Moros, M.; Idiago-López, J.; Asín, L.; Moreno-Antolín, E.; Beola, L.; Grazú, V.; Fratila, R. M.; Gutiérrez, L.; de la Fuente, J. M. Triggering Antitumoural Drug Release and Gene Expression by Magnetic Hyperthermia. Adv. Drug Delivery Rev. 2019, 138, 326– 343,  DOI: 10.1016/j.addr.2018.10.004
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    13
    Triggering antitumoural drug release and gene expression by magnetic hyperthermia
    Moros, Maria; Idiago-Lopez, Javier; Asin, Laura; Moreno-Antolin, Eduardo; Beola, Lilianne; Grazu, Valeria; Fratila, Raluca M.; Gutierrez, Lucia; de la Fuente, Jesus Martinez
    Advanced Drug Delivery Reviews (2019), 138 (), 326-343CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)
    A review. Magnetic nanoparticles (MNPs) are promising tools for a wide array of biomedical applications. One of their most outstanding properties is the ability to generate heat when exposed to alternating magnetic fields, usually exploited in magnetic hyperthermia therapy of cancer. In this contribution, we provide a crit. of the use of MNPs and magnetic hyperthermia as drug release and gene expression triggers for cancer therapy. Several strategies for the release of chemotherapeutic drugs from thermo-responsive matrixes are discussed, providing representative examples of their application at different levels (from proof of concept to in vivo applications). The potential of magnetic hyperthermia to promote in situ expression of therapeutic genes using vectors that contain heat-responsive promoters is also ed in the context of cancer gene therapy.
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  14. 14
    Mai, B. T.; Balakrishnan, P. B.; Barthel, M. J.; Piccardi, F.; Niculaes, D.; Marinaro, F.; Fernandes, S.; Curcio, A.; Kakwere, H.; Autret, G.; Cingolani, R.; Gazeau, F.; Pellegrino, T. Thermoresponsive Iron Oxide Nanocubes for an Effective Clinical Translation of Magnetic Hyperthermia and Heat-Mediated Chemotherapy. ACS Appl. Mater. Interfaces 2019, 11, 5727– 5739,  DOI: 10.1021/acsami.8b16226
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    14
    Thermoresponsive Iron Oxide Nanocubes for an Effective Clinical Translation of Magnetic Hyperthermia and Heat-Mediated Chemotherapy
    Mai Binh T; Balakrishnan Preethi B; Barthel Markus J; Piccardi Federica; Niculaes Dina; Marinaro Federica; Fernandes Soraia; Curcio Alberto; Kakwere Hamilton; Cingolani Roberto; Pellegrino Teresa; Mai Binh T; Balakrishnan Preethi B; Niculaes Dina; Autret Gwennhael; Gazeau Florence
    ACS applied materials & interfaces (2019), 11 (6), 5727-5739 ISSN:.
    The use of magnetic nanoparticles in oncothermia has been investigated for decades, but an effective combination of magnetic nanoparticles and localized chemotherapy under clinical magnetic hyperthermia (MH) conditions calls for novel platforms. In this study, we have engineered magnetic thermoresponsive iron oxide nanocubes (TR-cubes) to merge MH treatment with heat-mediated drug delivery, having in mind the clinical translation of the nanoplatform. We have chosen iron oxide based nanoparticles with a cubic shape because of their outstanding heat performance under MH clinical conditions, which makes them benchmark agents for MH. Accomplishing a surface-initiated polymerization of strongly interactive nanoparticles such as our iron oxide nanocubes, however, remains the main challenge to overcome. Here, we demonstrate that it is possible to accelerate the growth of a polymer shell on each nanocube by simple irradiation of a copper-mediated polymerization with a ultraviolet light (UV) light, which both speeds up the polymerization and prevents nanocube aggregation. Moreover, we demonstrate herein that these TR-cubes can carry chemotherapeutic doxorubicin (DOXO-loaded-TR-cubes) without compromising their thermoresponsiveness both in vitro and in vivo. In vivo efficacy studies showed complete tumor suppression and the highest survival rate for animals that had been treated with DOXO-loaded-TR-cubes, only when they were exposed to MH. The biodistribution of intravenously injected TR-cubes showed signs of renal clearance within 1 week and complete clearance after 5 months. This biomedical platform works under clinical MH conditions and at a low iron dosage, which will enable the translation of dual MH/heat-mediated chemotherapy, thus overcoming the clinical limitation of MH: i.e., being able to monitor tumor progression post-MH-treatment by magnetic resonance imaging (MRI).
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  15. 15
    Fernandes, S.; Fernandez, T.; Metze, S.; Balakrishnan, P. B.; Mai, B. T.; Conteh, J.; De Mei, C.; Turdo, A.; Di Franco, S.; Stassi, G. Magnetic Nanoparticle-Based Hyperthermia Mediates Drug Delivery and Impairs the Tumorigenic Capacity of Quiescent Colorectal Cancer Stem Cells. ACS Appl. Mater. Interfaces 2021, 13, 15959– 15972,  DOI: 10.1021/acsami.0c21349
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    15
    Magnetic Nanoparticle-Based Hyperthermia Mediates Drug Delivery and Impairs the Tumorigenic Capacity of Quiescent Colorectal Cancer Stem Cells
    Fernandes, Soraia; Fernandez, Tamara; Metze, Sabrina; Balakrishnan, Preethi B.; Mai, Binh T.; Conteh, John; De Mei, Claudia; Turdo, Alice; Di Franco, Simone; Stassi, Giorgio; Todaro, Matilde; Pellegrino, Teresa
    ACS Applied Materials & Interfaces (2021), 13 (14), 15959-15972CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
    Cancer stem cells (CSCs) are the tumor cell subpopulation responsible for resistance to chemotherapy, tumor recurrence, and metastasis. An efficient therapy must act on low proliferating quiescent-CSCs (q-CSCs). We here investigate the effect of magnetic hyperthermia (MHT) in combination with local chemotherapy as a dual therapy to inhibit patient-derived colorectal qCR-CSCs. We apply iron oxide nanocubes as MHT heat mediators, coated with a thermoresponsive polymer (TR-Cubes) and loaded with DOXO (TR-DOXO) as a chemotherapeutic agent. The thermoresponsive polymer releases DOXO only at a temp. above 44°C. In colony-forming assays, the cells exposed to TR-Cubes with MHT reveal that qCR-CSCs struggle to survive the heat damage and, with a due delay, restart the division of dormant cells. The eradication of qCR-CSCs with a complete stop of the colony formation was achieved only with TR-DOXO when exposed to MHT. The in vivo tumor formation study confirms the combined effects of MHT with heat-mediated drug release: only the group of animals that received the CR-CSCs pretreated, in vitro, with TR-DOXO and MHT lacked the formation of tumor even after several months. For DOXO-resistant CR-CSCs cells, the same results were shown, in vitro, when choosing the drug oxaliplatin rather than DOXO and applying MHT. These findings emphasize the potential of our nanoplatforms as an effective patient-personalized cancer treatment against qCR-CSCs.
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    Lee, J. H.; Chen, K. J.; Noh, S. H.; Garcia, M. A.; Wang, H.; Lin, W. Y.; Jeong, H.; Kong, B. J.; Stout, D. B.; Cheon, J. On-Demand Drug Release System for in Vivo Cancer Treatment through Self-Assembled Magnetic Nanoparticles. Angew. Chem., Int. Ed. Engl. 2013, 125, 4480– 4484,  DOI: 10.1002/anie.201207721
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    Guisasola, E.; Baeza, A.; Talelli, M.; Arcos, D.; Moros, M.; de la Fuente, J. M.; Vallet-Regí, M. Magnetic-Responsive Release Controlled by Hot Spot Effect. Langmuir 2015, 31, 12777– 12782,  DOI: 10.1021/acs.langmuir.5b03470
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    Magnetic-Responsive Release Controlled by Hot Spot Effect
    Guisasola, Eduardo; Baeza, Alejandro; Talelli, Marina; Arcos, Daniel; Moros, Maria; de la Fuente, Jesus M.; Vallet-Regi, Maria
    Langmuir (2015), 31 (46), 12777-12782CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
    Magnetically triggered drug delivery nanodevices have attracted great attention in nanomedicine, as they can feature as smart carriers releasing their payload at clinician's will. The key principle of these devices is based on the properties of magnetic cores to generate thermal energy in the presence of an alternating magnetic field. Then, the temp. increase triggers the drug release. Despite this potential, the rapid heat dissipation in living tissues is a serious hindrance for their clin. application. It is hypothesized that magnetic cores could act as hot spots, this is, produce enough heat to trigger the release without the necessity to increase the global temp. Herein, a nanocarrier has been designed to respond when the temp. reaches 43 °C. This material has been able to release its payload under an alternating magnetic field without the need of increasing the global temp. of the environment, proving the efficacy of the hot spot mechanism in magnetic-responsive drug delivery devices.
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    Cazares-Cortes, E.; Nerantzaki, M.; Fresnais, J.; Wilhelm, C.; Griffete, N.; Ménager, C. Magnetic Nanoparticles Create Hot Spots in Polymer Matrix for Controlled Drug Release. Nanomaterials 2018, 8, 850,  DOI: 10.3390/nano8100850
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    18
    Magnetic nanoparticles create hot spots in polymer matrix for controlled drug release
    Cazares-Cortes, Esther; Nerantzaki, Maria; Fresnais, Jerome; Wilhelm, Claire; Griffete, Nebewia; Menager, Christine
    Nanomaterials (2018), 8 (10), 850/1-850/11CODEN: NANOKO; ISSN:2079-4991. (MDPI AG)
    Herein, original magnetic drug delivery nanomaterials for cancer therapy are developed and compared, with the purpose to show active control over drug release by using an alternative magnetic field (AMF). The rationale is to combine polymers and superparamagnetic nanoparticles to trigger such drug release under AMF. Two magnetic nanosystems are thus presented: magnetic nanogels made of thermosensitive and biocompatible polymers and core-shell nanoparticles with a magnetic core and a molecularly imprinted polymer as shell. Both encapsulate doxorubicin (DOX) and the DOX controlled release was investigated in vitro and in cells under AMF excitation. It confirms that the local heat profile at the vicinity of the iron oxide core can be used for the DOX controlled release. It also shows that both nanosystems help delivering more DOX inside the cells compared to internalization of free DOX. Finally, the DOX intracellular release could be remotely triggered under AMF, in athermal conditions, thus enhancing DOX cytotoxicity.
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    Riedinger, A.; Guardia, P.; Curcio, A.; Garcia, M. A.; Cingolani, R.; Manna, L.; Pellegrino, T. Subnanometer Local Temperature Probing and Remotely Controlled Drug Release Based on Azo-Functionalized Iron Oxide Nanoparticles. Nano Lett. 2013, 13, 2399– 2406,  DOI: 10.1021/nl400188q
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    Subnanometer local temperature probing and remotely controlled drug release based on azo-functionalized iron oxide nanoparticles
    Riedinger, Andreas; Guardia, Pablo; Curcio, Alberto; Garcia, Miguel A.; Cingolani, Roberto; Manna, Liberato; Pellegrino, Teresa
    Nano Letters (2013), 13 (6), 2399-2406CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
    Local heating can be produced by iron oxide nanoparticles (IONPs) when exposed to an alternating magnetic field (AMF). To measure the temp. profile at the nanoparticle surface with a subnanometer resoln., here we present a mol. temp. probe based on the thermal decompn. of a thermo-sensitive mol., namely, azobis[N-(2-carboxyethyl)-2-methylpropionamidine]. Fluoresceineamine (FA) was bound to the azo mol. at the IONP surface functionalized with poly(ethylene glycol) (PEG) spacers of different mol. wts. Significant local heating, with a temp. increase up to 45°, was found at distances below 0.5 nm from the surface of the nanoparticle, which decays exponentially with increasing distance. Furthermore, the temp. increase was found to scale linearly with the applied field at all distances. We implemented these findings in an AMF-triggered drug release system in which doxorubicin was covalently linked at different distances from the IONP surface bearing the same thermo-labile azo mol. We demonstrated the AMF triggered distance-dependent release of the drug in a cytotoxicity assay on KB cancer cells.
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    Thomas, C. R.; Ferris, D. P.; Lee, J.-H.; Choi, E.; Cho, M. H.; Kim, E. S.; Stoddart, J. F.; Shin, J.-S.; Cheon, J.; Zink, J. I. Noninvasive Remote-Controlled Release of Drug Molecules in Vitro Using Magnetic Actuation of Mechanized Nanoparticles. J. Am. Chem. Soc. 2010, 132, 10623– 10625,  DOI: 10.1021/ja1022267
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    Noninvasive Remote-Controlled Release of Drug Molecules in Vitro Using Magnetic Actuation of Mechanized Nanoparticles
    Thomas, Courtney R.; Ferris, Daniel P.; Lee, Jae-Hyun; Choi, Eunjoo; Cho, Mi Hyeon; Kim, Eun Sook; Stoddart, J. Fraser; Shin, Jeon-Soo; Cheon, Jinwoo; Zink, Jeffrey I.
    Journal of the American Chemical Society (2010), 132 (31), 10623-10625CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Mesoporous silica nanoparticles are useful nanomaterials that have demonstrated the ability to contain and release cargos with mediation by gatekeepers. Magnetic nanocrystals have the ability to exhibit hyperthermic effects when placed in an oscillating magnetic field. In a system combining these two materials and a thermally sensitive gatekeeper, a unique drug delivery system can be produced. A novel material that incorporates zinc-doped iron oxide nanocrystals within a mesoporous silica framework that has been surface-modified with pseudorotaxanes is described. Upon application of an AC magnetic field, the nanocrystals generate local internal heating, causing the mol. machines to disassemble and allowing the cargos (drugs) to be released. When breast cancer cells (MDA-MB-231) were treated with doxorubicin-loaded particles and exposed to an AC field, cell death occurred. This material promises to be a noninvasive, externally controlled drug delivery system with cancer-killing properties.
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    Ruiz-Hernandez, E.; Baeza, A.; Vallet-Regi, M. Smart Drug Delivery through DNA/Magnetic Nanoparticle Gates. ACS Nano 2011, 5, 1259– 1266,  DOI: 10.1021/nn1029229
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    Smart Drug Delivery through DNA/Magnetic Nanoparticle Gates
    Ruiz-Hernandez, Eduardo; Baeza, Alejandro; Vallet-Regi, Maria
    ACS Nano (2011), 5 (2), 1259-1266CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    Mesoporous silica nanoparticles can be modified to perform on-demand stimuli-responsive dosing of therapeutic mols. The silica network was loaded with iron oxide superparamagnetic nanocrystals, providing the potential to perform targeting and magnetic resonance imaging. Single-stranded DNA was immobilized onto the material surface. The complementary DNA sequence was then attached to magnetic nanoparticles. The present work demonstrates that DNA/magnetic nanoparticle conjugates are able to cap the pores of the magnetic silica particles upon hybridization of both DNA strands. Progressive double-stranded DNA melting as a result of temp. increase gave rise to uncapping and the subsequent release of a mesopore-filled model drug, fluorescein. The reversibility of DNA linkage results in an "on-off" release mechanism. Moreover, the magnetic component of the whole system allows reaching hyperthermic temps. (42-47 °C) under an alternating magnetic field. This feature leaves open the possibility of a remotely triggered drug delivery. Furthermore, due to its capacity to increase the temp. of the surrounding media, this multifunctional device could play an important role in the development of advanced drug delivery systems for thermochemotherapy against cancer.
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    N’Guyen, T. T.; Duong, H. T.; Basuki, J.; Montembault, V.; Pascual, S.; Guibert, C.; Fresnais, J.; Boyer, C.; Whittaker, M. R.; Davis, T. P. Functional Iron Oxide Magnetic Nanoparticles with Hyperthermia-Induced Drug Release Ability by Using a Combination of Orthogonal Click Reactions. Angew. Chem., Int. Ed. Engl. 2013, 125, 14402– 14406,  DOI: 10.1002/anie.201306724
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    Hammad, M.; Nica, V.; Hempelmann, R. On-Command Controlled Drug Release by Diels-Alder Reaction Using Bi-Magnetic Core/Shell Nano-Carriers. Colloids Surf., B 2017, 150, 15– 22,  DOI: 10.1016/j.colsurfb.2016.11.005
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    On-command controlled drug release by Diels-Alder reaction using Bi-magnetic core/shell nano-carriers
    Hammad, Mohaned; Nica, Valentin; Hempelmann, Rolf
    Colloids and Surfaces, B: Biointerfaces (2017), 150 (), 15-22CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)
    A novel bi-functional thermo-responsive system, consisting of core/shell bi-magnetic nanoparticles with furan surface functionality, is bonded with N-(2-Carboxyethyl)maleimide through Diels-Alder reaction. The chemotherapeutics doxorubicin is attached onto the surface, with a high loading efficiency of 92%. This system with high responsiveness to a high frequency external alternating magnetic field shows a very good therapeutic efficiency in hyperthermia and drug release at relatively low temps. (50°C). Polyhedron-shaped bi-magnetic nanoparticles ([email protected]) exhibit a significant increase of the specific energy absorption rate up to 455 W/g compared with the core nanoparticles (200 W/g). Real-time florescence spectroscopy studies demonstrate rapid release of doxorubicin up to 50% in 5 min and up to 92% after 15 min upon exposure to high frequency external alternating magnetic field. The stability is evaluated for 8 wk in phosphate buffer saline with a doxorubicin payload of 85%. In vitro studies using std. MTT cell assays with HeLa and Hep G2 lines prove an excellent biocompatibility with about 90% of cell viability after 24 h of treatment within the highest concn. of functionalized magnetic nanoparticles (200μg/mL). The results indicate a controlled drug release mediated by thermo-responsive switching under applied alternating magnetic field.
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    Guldris, N.; Gallo, J.; García-Hevia, L.; Rivas, J.; Bañobre-López, M.; Salonen, L. M. Orthogonal Clickable Iron Oxide Nanoparticle Platform for Targeting, Imaging, and on-Demand Release. Chem. – A Eur. J. 2018, 24, 8624– 8631,  DOI: 10.1002/chem.201800389
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    Orthogonal Clickable Iron Oxide Nanoparticle Platform for Targeting, Imaging, and On-Demand Release
    Guldris, Noelia; Gallo, Juan; Garcia-Hevia, Lorena; Rivas, Jose; Banobre-Lopez, Manuel; Salonen, Laura M.
    Chemistry - A European Journal (2018), 24 (34), 8624-8631CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A versatile iron oxide nanoparticle platform is reported that can be orthogonally functionalized to obtain highly derivatized nanomaterials required for a wide variety of applications, such as drug delivery, targeted therapy, or imaging. Facile functionalization of the nanoparticles with two ligands contg. isocyanate moieties allows for high coverage of the surface with maleimide and alkyne groups. As a proof-of-principle, the nanoparticles were subsequently functionalized with a fluorophore as a drug model and with biotin as a targeting ligand towards tumor cells through Diels-Alder and azide-alkyne cycloaddn. reactions, resp. The thermoreversibility of the Diels-Alder product was exploited to induce the on-demand release of the loaded mols. by magnetic hyperthermia. Addnl., the nanoparticles were shown to target cancer cells through in vitro expts., as analyzed by magnetic resonance imaging.
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    Wang, L. L.; Balakrishnan, A.; Bigall, N. C.; Candito, D.; Miethe, J. F.; Seidel, K.; Xie, Y.; Ott, M.; Kirschning, A. A Bio-Chemosynthetic Approach to Superparamagnetic Iron Oxide–Ansamitocin Conjugates for Use in Magnetic Drug Targeting. Chem. – Eur. J. 2017, 23, 2265– 2270,  DOI: 10.1002/chem.201604903
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    A Bio-Chemosynthetic Approach to Superparamagnetic Iron Oxide-Ansamitocin Conjugates for Use in Magnetic Drug Targeting
    Wang, Liang-Liang; Balakrishnan, Asha; Bigall, Nadja-Carola; Candito, David; Miethe, Jan Frederick; Seidel, Katja; Xie, Yu; Ott, Michael; Kirschning, Andreas
    Chemistry - A European Journal (2017), 23 (10), 2265-2270CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A combination of mutasynthesis using a mutant strain of A. pretiosum blocked in the biosynthesis of amino-hydroxybenzoic acid (AHBA) and semisynthesis relying on a Stille cross-coupling step provided access to new ansamitocin derivs. of which one was attached by a thermolabile linker to nanostructured iron oxide particles. When exposed to an oscillating electromagnetic field the resulting iron oxide/ansamitocin conjugate 19 heats up in an aq. suspension and the ansamitocin deriv. 16 is released by means of a retro-Diels-Alder reaction. It exerts strong antiproliferative activity (IC50=4.8 ng mg-1) in mouse fibroblasts. These new types of conjugates have the potential for combating cancer through hyperthermia and chemotherapy using an electromagnetic external trigger.
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    Zetterlund, P. B.; Thickett, S. C.; Perrier, S.; Bourgeat-Lami, E.; Lansalot, M. Controlled/Living Radical Polymerization in Dispersed Systems: An Update. Chem. Rev. 2015, 115, 9745– 9800,  DOI: 10.1021/cr500625k
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    Controlled/Living Radical Polymerization in Dispersed Systems: An Update
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    Chemical Reviews (Washington, DC, United States) (2015), 115 (18), 9745-9800CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review. As alluded to in the Introduction, and as made evident throughout this review, the field of CLRP (controlled/living radical polymn.) in dispersed systems has matured significantly over the past decade. It is now relatively well understood how to best implement CLRP in various (aq.) heterogeneous systems, although challenges still remain. Despite the progress over the past decade,thereare still gaps in fundamental mechanistic understanding, for example, in regard to detailed effects of compartmentalization on CLRP.
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    Matyjaszewski, K.; Spanswick, J. Controlled/Living Radical Polymerization. Mater. Today 2005, 8, 26– 33,  DOI: 10.1016/S1369-7021(05)00745-5
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    Controlled/living radical polymerization
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    Materials Today (Oxford, United Kingdom) (2005), 8 (3), 26-33CODEN: MTOUAN; ISSN:1369-7021. (Elsevier Ltd.)
    A review. Until a little more than a decade ago, controlled/living radical polymn. (CRP) would have been an oxymoron. Full control over all aspects of radical polymn. was deemed well-nigh impossible because radical termination reactions occur at diffusion-controlled rates. However, there are now several procedures for controlling radical polymn., and corporations are introducing products based on CRP into numerous high-value markets. This review briefly summarizes the evolution of CRP, describes some of the materials that can now be prepd., and highlights some of the commercialization efforts currently underway.
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    Boyer, C.; Bulmus, V.; Davis, T. P.; Ladmiral, V.; Liu, J.; Perrier, S. Bioapplications of Raft Polymerization. Chem. Rev. 2009, 109, 5402– 5436,  DOI: 10.1021/cr9001403
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    Bioapplications of RAFT Polymerization
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    Chemical Reviews (Washington, DC, United States) (2009), 109 (11), 5402-5436CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review with major subsections entitled Introduction, Functional Polymers Obtained by RAFT, Bioconjugates, Drug Delivery, and Surface Modification by RAFT Polymn. for Biol. Applications.
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    Macromolecules (Washington, DC, United States) (2017), 50 (19), 7433-7447CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
    A review. This Perspective summarizes the features and limitations of reversible addn.-fragmentation chain transfer (RAFT) polymn., highlighting its strengths and weaknesses, as our understanding of the process, from both a mechanistic and an application point of view, has matured over the past 20 years. It is aimed at both experts in the field and newcomers, including undergraduate and postgraduate students, as well as nonexperts in polymn. who are interested in developing their own polymeric structures by exploiting the simple setup of a RAFT polymn.
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    Pindur, U.; Lutz, G.; Otto, C. Acceleration and Selectivity Enhancement of Diels-Alder Reactions by Special and Catalytic Methods. Chem. Rev. 1993, 93, 741– 761,  DOI: 10.1021/cr00018a006
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    Acceleration and selectivity enhancement of Diels-Alder reactions by special and catalytic methods
    Pindur, Ulf; Lutz, Gundula; Otto, Christian
    Chemical Reviews (Washington, DC, United States) (1993), 93 (2), 741-61CODEN: CHREAY; ISSN:0009-2665.
    Acceleration and selectivity enhancement of Diels-Alder reactions by special and catalytic methods is reviewed with 121 refs.
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    Tasdelen, M. A. Diels–Alder “Click” Reactions: Recent Applications in Polymer and Material Science. Polym. Chem. 2011, 2, 2133– 2145,  DOI: 10.1039/c1py00041a
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    Diels-Alder "click" reactions: recent applications in polymer and material science
    Tasdelen, Mehmet Atilla
    Polymer Chemistry (2011), 2 (10), 2133-2145CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)
    A review. The "click" chem. concept is based on utilizing rapid reactions which are efficient, versatile, and selective. Indeed, Diels-Alder (DA) reactions fulfill most of the requirements for the "click" chem. concept. The authors discuss the recent reports concerned with the use of DA "click" reactions in the synthesis of various macromol. architectures (homopolymers, block and graft copolymers, telechelic polymer), bioconjugates (nucleic acid, peptides), and hybrid materials.
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    Khan, N.; Halder, S.; Gunjan, S.; Prasad, T. A Review on Diels-Alder Based Self-Healing Polymer Composites. IOP Conf. Ser.: Mater. Sci. Eng. 2018, 377, 012007  DOI: 10.1088/1757-899X/377/1/012007
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    A review on Diels-Alder based self-healing polymer composites
    Khan, N. I.; Halder, S.; Gunjan, S. B.; Prasad, T.
    IOP Conference Series: Materials Science and Engineering (2018), 377 (International Conference on Mechanical, Materials and Renewable Energy, 2017), 012007/1-012007/9CODEN: ICSMGW; ISSN:1757-899X. (IOP Publishing Ltd.)
    A review. Self-healing polymers are the materials which can heal the internal cracks or damages automatically without any external intervention. The concept of self-healing has been derived from the biol. systems such as human bone or skin which can heal automatically. This paper reviews the self-healing polymers based on Diels-Alder reaction where diene and dienophile groups form reversible covalent bond between them in the polymer matrix. A comprehensive review on Diels-Alder based self-healing composites reinforced with nanofillers from the last decade have been reported here. The present status followed by future scope in this area has also been discussed briefly at the end of this review.
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    Mai, B. T.; Barthel, M.; Marotta, R.; Pellegrino, T. Crosslinked Ph-Responsive Polymersome Via Diels-Alder Click Chemistry: A Reversible Ph-Dependent Vesicular Nanosystem. Polymer 2019, 165, 19– 27,  DOI: 10.1016/j.polymer.2019.01.022
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    Crosslinked pH-responsive polymersome via Diels-Alder click chemistry: A reversible pH-dependent vesicular nanosystem
    Mai, Binh T.; Barthel, Markus; Marotta, Roberto; Pellegrino, Teresa
    Polymer (2019), 165 (), 19-27CODEN: POLMAG; ISSN:0032-3861. (Elsevier Ltd.)
    Herein, we have developed pH-responsive shape-persistent polymersomes made of well-defined amphiphilic poly(ethylene oxide)-block-poly(diisopropylaminoethyl methacrylate-co-furfuryl methacrylate)s PEO-b-P(DPA-co-FMA) by exploiting Diels-Alder chem. as a robust and simple crosslinking method. Using Photo-induced Copper Mediated Reversible Deactivation Radical Polymn., we synthesized PEO-b-P(DPA-co-FMA) with optimal block ratios that favor the formation of polymersomes in aq. media having pH-responsive P(DPA-co-FMA) membranes. Owing to the existence of furfuryl pendant groups within the polymersome membranes, the crosslinking of pH-responsive P(DPA-co-FMA) chains can be achieved via Diels-Alder chem. Interestingly, the resulting crosslinked polymersomes swell when the pH in the soln. is decreased so that it lies in a biol. relevant range, as was demonstrated by cryogenic transmission electron microscopy. Here, the polymersomes' ability to swell can be controlled by adjusting the amt. of crosslinker. A min. threshold of crosslinking d. is needed for the polymersomes to swell while an excess amt. of crosslinker quenched their ability to swell. Furthermore, crosslinked polymersomes are capable of encapsulating hydrophilic model drug, such as Rhodamine B. At pH 7.20, due to the compact and hydrophobic membrane, the diffusion of the dye from the interior of the polymersomes to the media is minimized, while the pronation of PDPA at an acidic pH of 4.00, enables a permeable membrane, allowing the loaded cargo to leak much more quickly. The shape-persistent polymersomes that we developed herein, are a promising nano-platform for use in drug delivery applications.
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    Goussé, C.; Gandini, A.; Hodge, P. Application of the Diels– Alder Reaction to Polymers Bearing Furan Moieties. 2. Diels– Alder and Retro-Diels– Alder Reactions Involving Furan Rings in Some Styrene Copolymers. Macromolecules 1998, 31, 314– 321,  DOI: 10.1021/ma9710141
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    Application of the Diels-Alder Reaction to Polymers Bearing Furan Moieties. 2. Diels-Alder and Retro-Diels-Alder Reactions Involving Furan Rings in Some Styrene Copolymers
    Gousse, Cecile; Gandini, Alessandro; Hodge, Philip
    Macromolecules (1998), 31 (2), 314-321CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
    Styrene copolymers contg. various amts. of a novel comonomer bearing a pendant furan ring were synthesized and characterized before being submitted to Diels-Alder reactions with either a monomaleimide or a bismaleimide. Spectroscopic evidence, supported by data from model compds., indicated that the resulting linear and crosslinked products contained extensive percentages of adduct structures formed from the furan moieties. Both types of materials were then heated in a solvent contg. a large excess of 2-methylfuran in order to induce the retro-Diels-Alder and the coupling of the released maleimides with the furanic additive. The reaction proceeded as expected and the original copolymers could be recovered from the treatment. The interest in the general strategy reported here resides in the possibility of recycling crosslinked polymers by a simple thermal treatment conducted in the presence of a suitable trap.
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    Dispinar, T.; Sanyal, R.; Sanyal, A. A Diels-Alder/Retro Diels-Alder Strategy to Synthesize Polymers Bearing Maleimide Side Chains. J. Polym. Sci., Part A: Polym. Chem. 2007, 45, 4545– 4551,  DOI: 10.1002/pola.22299
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    A diels-alder/retro diels-alder strategy to synthesize polymers bearing maleimide side chains
    Dispinar, Tugba; Sanyal, Rana; Sanyal, Amitav
    Journal of Polymer Science, Part A: Polymer Chemistry (2007), 45 (20), 4545-4551CODEN: JPACEC; ISSN:0887-624X. (John Wiley & Sons, Inc.)
    Polymers contg. thiol-reactive maleimide groups on their side chains were synthesized by utilization of a novel methacrylate monomer contg. a masked maleimide. Diels-Alder reaction between furan and maleimide was adapted for the protection of the reactive maleimide double bond prior to polymn. AIBN initiated free radical polymn. was utilized for synthesis of copolymers contg. masked maleimide groups. No unmasking of the maleimide group was evident under the polymn. conditions. The maleimide groups in the side chain of the polymers were unmasked into their reactive from by utilization of retro Diels-Alder reaction. This cycloreversion was monitored by thermo gravimetric anal. (TGA), DSC, and 1H and 13C NMR spectroscopy.
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    Discekici, E. H.; St. Amant, A. H.; Nguyen, S. N.; Lee, I.-H.; Hawker, C. J.; Read de Alaniz, J. Endo and Exo Diels–Alder Adducts: Temperature-Tunable Building Blocks for Selective Chemical Functionalization. J. Am. Chem. Soc. 2018, 140, 5009– 5013,  DOI: 10.1021/jacs.8b01544
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    Endo and Exo Diels-Alder Adducts: Temperature-Tunable Building Blocks for Selective Chemical Functionalization
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    Journal of the American Chemical Society (2018), 140 (15), 5009-5013CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The development and application of a novel endo furan-protected maleimide building block is reported. The endo isomer undergoes deprotection at temps. ∼50 °C below the exo deriv. This enables a simple and powerful approach to quant. and selectively introduce functional maleimide groups via temp. modulation.
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    Oliveira, B.; Guo, Z.; Bernardes, G. Inverse Electron Demand Diels–Alder Reactions in Chemical Biology. Chem. Soc. Rev. 2017, 46, 4895– 4950,  DOI: 10.1039/C7CS00184C
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    Oliveira, B. L.; Guo, Z.; Bernardes, G. J. L.
    Chemical Society Reviews (2017), 46 (16), 4895-4950CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    The emerging inverse electron demand Diels-Alder (IEDDA) reaction stands out from other bioorthogonal reactions by virtue of its unmatchable kinetics, excellent orthogonality and biocompatibility. With the recent discovery of novel dienophiles and optimal tetrazine coupling partners, attention has now been turned to the use of IEDDA approaches in basic biol., imaging and therapeutics. Here we review this bioorthogonal reaction and its promising applications for live cell and animal studies. We first discuss the key factors that contribute to the fast IEDDA kinetics and describe the most recent advances in the synthesis of tetrazine and dienophile coupling partners. Both coupling partners have been incorporated into proteins for tracking and imaging by use of fluorogenic tetrazines that become strongly fluorescent upon reaction. Selected notable examples of such applications are presented. The exceptional fast kinetics of this catalyst-free reaction, even using low concns. of coupling partners, make it amenable for in vivo radiolabelling using pretargeting methodologies, which are also discussed. Finally, IEDDA reactions have recently found use in bioorthogonal decaging to activate proteins or drugs in gain-of-function strategies. We conclude by showing applications of the IEDDA reaction in the construction of biomaterials that are used for drug delivery and multimodal imaging, among others. The use and utility of the IEDDA reaction is interdisciplinary and promises to revolutionize chem. biol., radiochem. and materials science.
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    Guardia, P.; Di Corato, R.; Lartigue, L.; Wilhelm, C.; Espinosa, A.; Garcia-Hernandez, M.; Gazeau, F.; Manna, L.; Pellegrino, T. Water-Soluble Iron Oxide Nanocubes with High Values of Specific Absorption Rate for Cancer Cell Hyperthermia Treatment. ACS Nano 2012, 6, 3080– 3091,  DOI: 10.1021/nn2048137
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    Water-Soluble Iron Oxide Nanocubes with High Values of Specific Absorption Rate for Cancer Cell Hyperthermia Treatment
    Guardia, Pablo; Di Corato, Riccardo; Lartigue, Lenaic; Wilhelm, Claire; Espinosa, Ana; Garcia-Hernandez, Mar; Gazeau, Florence; Manna, Liberato; Pellegrino, Teresa
    ACS Nano (2012), 6 (4), 3080-3091CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    Iron oxide nanocrystals (IONCs) are appealing heat mediator nanoprobes in magnetic-mediated hyperthermia for cancer treatment. Here, specific absorption rate (SAR) values are reported for cube-shaped water-sol. IONCs prepd. by a one-pot synthesis approach in a size range between 13 and 40 nm. The SAR values were detd. as a function of frequency and magnetic field applied, also spanning tech. conditions which are considered biomedically safe for patients. Among the different sizes tested, IONCs with an av. diam. of 19 ± 3 nm had significant SAR values in clin. conditions and reached SAR values up to 2452 W/gFe at 520 kHz and 29 kAm-1, which is one of the highest values so far reported for IONCs. In vitro trials carried out on KB cancer cells treated with IONCs of 19 nm have shown efficient hyperthermia performance, with cell mortality of about 50% recorded when an equil. temp. of 43 °C was reached after 1 h of treatment.
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    Kolosnjaj-Tabi, J.; Di Corato, R.; Lartigue, L.; Marangon, I.; Guardia, P.; Silva, A. K.; Luciani, N.; Clement, O.; Flaud, P.; Singh, J. V. Heat-Generating Iron Oxide Nanocubes: Subtle “Destructurators” of the Tumoral Microenvironment. ACS Nano 2014, 8, 4268– 4283,  DOI: 10.1021/nn405356r
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    Heat-Generating Iron Oxide Nanocubes: Subtle "Destructurators" of the Tumoral Microenvironment
    Kolosnjaj-Tabi, Jelena; Di Corato, Riccardo; Lartigue, Lenaic; Marangon, Iris; Guardia, Pablo; Silva, Amanda K. A.; Luciani, Nathalie; Clement, Olivier; Flaud, Patrice; Singh, Jaykrishna V.; Decuzzi, Paolo; Pellegrino, Teresa; Wilhelm, Claire; Gazeau, Florence
    ACS Nano (2014), 8 (5), 4268-4283CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    Several studies propose nanoparticles for tumor treatment, yet little is known about the fate of nanoparticles and intimate interactions with the heterogeneous and ever-evolving tumor environment. The latter, rich in extracellular matrix, is responsible for poor penetration of therapeutics and represents a paramount issue in cancer therapy. Hence new strategies start aiming to modulate the neoplastic stroma. From this perspective, we assessed the efficacy of 19 nm PEG-coated iron oxide nanocubes with optimized magnetic properties to mediate mild tumor magnetic hyperthermia treatment. After injection of a low dose of nanocubes (700 μg of iron) into epidermoid carcinoma xenografts in mice, we monitored the effect of heating nanocubes on tumor environment. In comparison with the long-term fate after i.v. administration, we investigated spatiotemporal patterns of nanocube distribution, evaluated the evolution of cubes magnetic properties, and examd. nanoparticle clearance and degrdn. processes. While inside tumors nanocubes retained their magnetic properties and heating capacity throughout the treatment due to a mainly interstitial extracellular location, the particles became inefficient heaters after cell internalization and transfer to spleen and liver. Our multiscale anal. reveals that collagen-rich tumor extracellular matrix confines the majority of nanocubes. However, nanocube-mediated hyperthermia has the potential to "destructure" this matrix and improve nanoparticle and drug penetration into neoplastic tissue. This study provides insight into dynamic interactions between nanoparticles and tumor components under phys. stimulation and suggests that nanoparticle-mediated hyperthermia could be used to locally modify tumor stroma and thus improve drug penetration.
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    Espinosa, A.; Di Corato, R.; Kolosnjaj-Tabi, J.; Flaud, P.; Pellegrino, T.; Wilhelm, C. Duality of Iron Oxide Nanoparticles in Cancer Therapy: Amplification of Heating Efficiency by Magnetic Hyperthermia and Photothermal Bimodal Treatment. ACS Nano 2016, 10, 2436– 2446,  DOI: 10.1021/acsnano.5b07249
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    Duality of Iron Oxide Nanoparticles in Cancer Therapy: Amplification of Heating Efficiency by Magnetic Hyperthermia and Photothermal Bimodal Treatment
    Espinosa, Ana; Di Corato, Riccardo; Kolosnjaj-Tabi, Jelena; Flaud, Patrice; Pellegrino, Teresa; Wilhelm, Claire
    ACS Nano (2016), 10 (2), 2436-2446CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    The pursuit of innovative, multifunctional, more efficient, and safer treatments is a major challenge in preclin. nanoparticle-mediated thermotherapeutic research. Here, we report that iron oxide nanoparticles have the dual capacity to act as both magnetic and photothermal agents. We further explore every key aspect of this magnetophotothermal approach, choosing iron oxide nanocubes for their high efficiency for the magnetic hyperthermia modality itself. In aq. suspension, the nanocubes' exposure to both: an alternating magnetic field and near-IR laser irradn. (808 nm), defined as the DUAL-mode, amplifies the heating effect 2- to 5-fold by comparison with magnetic stimulation alone, yielding unprecedented heating powers (specific loss powers) up to 5000 W/g. In cancer cells, the laser excitation restores the optimal efficiency of magnetic hyperthermia, otherwise inhibited by intracellular confinement, resulting in a remarkable heating efficiency in the DUAL-mode (up to 15-fold amplification), with respect to the magnetophotothermal mode. As a consequence, the dual action yielded complete apoptosis-mediated cell death. In solid tumors in vivo, single-mode treatments (magnetic or laser hyperthermia) reduced tumor growth, while DUAL-mode treatment resulted in complete tumor regression, mediated by heat-induced tumoral cell apoptosis and massive denaturation of the collagen fibers, and a long-lasting thermal efficiency over repeated treatments.
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    Materia, M. E.; Guardia, P.; Sathya, A.; Pernia Leal, M.; Marotta, R.; Di Corato, R.; Pellegrino, T. Mesoscale Assemblies of Iron Oxide Nanocubes as Heat Mediators and Image Contrast Agents. Langmuir 2015, 31, 808– 816,  DOI: 10.1021/la503930s
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    Mesoscale Assemblies of Iron Oxide Nanocubes as Heat Mediators and Image Contrast Agents
    Materia, Maria Elena; Guardia, Pablo; Sathya, Ayyappan; Pernia Leal, Manuel; Marotta, Roberto; Di Corato, Riccardo; Pellegrino, Teresa
    Langmuir (2015), 31 (2), 808-816CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
    Iron oxide nanocubes (IONCs) represent one of the most promising iron-based nanoparticles for both magnetic resonance image (MRI) and magnetically mediated hyperthermia (MMH). Here, we have set a protocol to control the aggregation of magnetically interacting IONCs within a polymeric matrix in a so-called magnetic nanobead (MNB) having mesoscale size (200 nm). By the comparison with individual coated nanocubes, we elucidate the effect of the aggregation on the specific adsorption rates (SAR) and on the T1 and T2 relaxation times. We found that while SAR values decrease as IONCs are aggregated into MNBs but still keeping significant SAR values (200 W/g at 300 kHz), relaxation times show very interesting properties with outstanding values of r2/r1 ratio for the MNBs with respect to single IONCs.
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    Champagne, P.-O.; Westwick, H.; Bouthillier, A.; Sawan, M. Colloidal Stability of Superparamagnetic Iron Oxide Nanoparticles in the Central Nervous System: A Review. Nanomedicine 2018, 13, 1385– 1400,  DOI: 10.2217/nnm-2018-0021
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    Colloidal stability of superparamagnetic iron oxide nanoparticles in the central nervous system: a review
    Champagne, Pierre-Olivier; Westwick, Harrison; Bouthillier, Alain; Sawan, Mohamad
    Nanomedicine (London, United Kingdom) (2018), 13 (11), 1385-1400CODEN: NLUKAC; ISSN:1748-6963. (Future Medicine Ltd.)
    Superparamagnetic iron oxide nanoparticles (SPIONs) consist of nanosized metallic-based particles with unique magnetic properties. Their potential in both diagnostic and therapeutic applications in the CNS is at the source of an expanding body of the literature in recent years. Colloidal stability of nanoparticles represents their ability to resist aggregation and is a central aspect for the use of SPION in biol. environment such as the CNS. This review gives a comprehensive update of the recent developments and knowledge on the determinants of colloidal stability of SPIONs in the CNS. Factors leading to aggregate formation and the repercussions of colloidal instability of SPION are reviewed in detail pertaining to their use in the CNS.
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    Palui, G.; Aldeek, F.; Wang, W.; Mattoussi, H. Strategies for Interfacing Inorganic Nanocrystals with Biological Systems Based on Polymer-Coating. Chem. Soc. Rev. 2015, 44, 193– 227,  DOI: 10.1039/C4CS00124A
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    Strategies for interfacing inorganic nanocrystals with biological systems based on polymer-coating
    Palui, Goutam; Aldeek, Fadi; Wang, Wentao; Mattoussi, Hedi
    Chemical Society Reviews (2015), 44 (1), 193-227CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    A review. Interfacing inorg. nanoparticles and biol. systems with the aim of developing novel imaging and sensing platforms has generated great interest and much activity. However, the effectiveness of this approach hinges on the ability of the surface ligands to promote water-dispersion of the nanoparticles with long term colloidal stability in buffer media. These surface ligands protect the nanostructures from the harsh biol. environment, while allowing coupling to target mols., which can be biol. in nature (e.g., proteins and peptides) or exhibit specific photo-phys. characteristics (e.g., a dye or a redox-active mol.). Amphiphilic block polymers have provided researchers with versatile mol. platforms with tunable size, compn. and chem. properties. Hence, several groups have developed a wide range of polymers as ligands or micelle capsules to promote the transfer of a variety of inorg. nanomaterials to buffer media (including magnetic nanoparticles and semiconductor nanocrystals) and render them biocompatible. In this review, we first summarize the established synthetic routes to grow high quality nanocrystals of semiconductors, metals and metal oxides. We then provide a crit. evaluation of the recent developments in the design, optimization and use of various amphiphilic copolymers to surface functionalize the above nanocrystals, along with the strategies used to conjugate them to target biomols. We finally conclude by providing a summary of the most promising applications of these polymer-coated inorg. platforms in sensor design, and imaging of cells and tissues.
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    Ling, D.; Lee, N.; Hyeon, T. Chemical Synthesis and Assembly of Uniformly Sized Iron Oxide Nanoparticles for Medical Applications. Acc. Chem. Res. 2015, 48, 1276– 1285,  DOI: 10.1021/acs.accounts.5b00038
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    Chemical Synthesis and Assembly of Uniformly Sized Iron Oxide Nanoparticles for Medical Applications
    Ling, Daishun; Lee, Nohyun; Hyeon, Taeghwan
    Accounts of Chemical Research (2015), 48 (5), 1276-1285CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
    A review. Magnetic iron oxide nanoparticles have been extensively investigated for their various biomedical applications including diagnostic imaging, biol. sensing, drug, cell, and gene delivery, and cell tracking. Recent advances in the designed synthesis and assembly of uniformly sized iron oxide nanoparticles have brought innovation in the field of nanomedicine. This Account provides a review on the recent progresses in the controlled synthesis and assembly of uniformly sized iron oxide nanoparticles for medical applications. In particular, it focuses on three topics: stringent control of particle size during synthesis via the "heat-up" process, surface modification for the high stability and biocompatibility of the nanoparticles for diagnostic purposes, and assembly of the nanoparticles within polymers or mesoporous silica matrixes for theranostic applications. Using extremely small 3 nm sized iron oxide nanoparticles (ESION), a new nontoxic T1 MRI contrast agent was realized for high-resoln. MRI of blood vessels down to 0.2 mm. Ferrimagnetic iron oxide nanoparticles (FION) that are larger than 20 nm exhibit extremely large magnetization and coercivity values. The cells labeled with FIONs showed very high T2 contrast effect so that even a single cell can be readily imaged. Designed assembly of iron oxide nanoparticles with mesoporous silica and polymers was conducted to fabricate multifunctional nanoparticles for theranostic applications. Mesoporous silica nanoparticles are excellent scaffolds for iron oxide nanoparticles, providing magnetic resonance and fluorescence imaging modalities as well as the functionality of the drug delivery vehicle. Polymeric ligands could be designed to respond to various biol. stimuli such as pH, temp., and enzymic activity. For example, we fabricated tumor pH-sensitive magnetic nanogrenades (termed PMNs) composed of self-assembled iron oxide nanoparticles and pH-responsive ligands. They were utilized to visualize small tumors (<3 mm) via pH-responsive T1 MRI and fluorescence imaging. Also, superior photodynamic therapeutic efficacy in highly drug-resistant heterogeneous tumors was obsd. We expect that these multifunctional and bioresponsive nanoplatforms based on uniformly sized iron oxide nanoparticles will provide more unique theranostic approaches in clin. uses.
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    Wu, W.; Jiang, C. Z.; Roy, V. A. Designed Synthesis and Surface Engineering Strategies of Magnetic Iron Oxide Nanoparticles for Biomedical Applications. Nanoscale 2016, 8, 19421– 19474,  DOI: 10.1039/C6NR07542H
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    Designed synthesis and surface engineering strategies of magnetic iron oxide nanoparticles for biomedical applications
    Wu, Wei; Jiang, Chang Zhong; Roy, Vellaisamy A. L.
    Nanoscale (2016), 8 (47), 19421-19474CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
    A review. Iron oxide nanoparticles (NPs) hold great promise for future biomedical applications because of their magnetic properties as well as other intrinsic properties such as low toxicity, colloidal stability, and surface engineering capability. Numerous related studies on iron oxide NPs have been conducted. Recent progress in nanochem. has enabled fine control over the size, crystallinity, uniformity, and surface properties of iron oxide NPs. This review examines various synthetic approaches and surface engineering strategies for prepg. naked and functional iron oxide NPs with different physicochem. properties. Growing interest in designed and surface-engineered iron oxide NPs with multifunctionalities was explored in in vitro/in vivo biomedical applications, focusing on their combined roles in biosepn., as a biosensor, targeted-drug delivery, MR contrast agents, and magnetic fluid hyperthermia. This review outlines the limitations of extant surface engineering strategies and several developing strategies that may overcome these limitations. This study also details the promising future directions of this active research field.
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    Schubert, J.; Chanana, M. Coating Matters: Review on Colloidal Stability of Nanoparticles with Biocompatible Coatings in Biological Media, Living Cells and Organisms. Curr. Med. Chem. 2019, 25, 4556,  DOI: 10.2174/0929867325666180601101859
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    Garbin, V.; Crocker, J. C.; Stebe, K. J. Nanoparticles at Fluid Interfaces: Exploiting Capping Ligands to Control Adsorption, Stability and Dynamics. J. Colloid Interface Sci. 2012, 387, 1– 11,  DOI: 10.1016/j.jcis.2012.07.047
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    Nanoparticles at fluid interfaces: Exploiting capping ligands to control adsorption, stability and dynamics
    Garbin, Valeria; Crocker, John C.; Stebe, Kathleen J.
    Journal of Colloid and Interface Science (2012), 387 (1), 1-11CODEN: JCISA5; ISSN:0021-9797. (Elsevier B.V.)
    A review. Nanoparticle self-assembly at fluid-fluid interfaces has been traditionally exploited in emulsification, encapsulation, and oil recovery, and more recently in emerging applications including functional nanomaterials and biphasic catalysis. A review of the literature focusing on the open challenges that still hamper the broader applicability of this potentially transformative technol. is provided, and strategies to achieve improved control over interfacial self-assembly of nanoparticles are outlined. Means to promote spontaneous adsorption by tuning the interfacial energies of the nanoparticles with the fluids using capping ligands and the occurrence of energy barriers are discussed. The interactions between interfacial nanoparticles and how they affect the formation of equil. interfacial suspensions vs. non-equil. two-dimensional phases, such as weakly attractive glasses and gels, are discussed. Important differences with colloidal interactions in a bulk suspension arise due to the discontinuity in solvent properties at the interface. For instance, ligand brushes rearrange in asym. configurations, and thus play a significant role in detg. interparticle interactions. Finally, the link between interfacial microstructure and the dynamic response of particle-laden interfaces, including interfacial rheol. and the fate of nanoparticle monolayers upon out-of-plane deformation, are discussed.
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    Na, H. B.; Palui, G.; Rosenberg, J. T.; Ji, X.; Grant, S. C.; Mattoussi, H. Multidentate Catechol-Based Polyethylene Glycol Oligomers Provide Enhanced Stability and Biocompatibility to Iron Oxide Nanoparticles. ACS Nano 2012, 6, 389– 399,  DOI: 10.1021/nn203735b
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    Multidentate Catechol-Based Polyethylene Glycol Oligomers Provide Enhanced Stability and Biocompatibility to Iron Oxide Nanoparticles
    Na, Hyon Bin; Palui, Goutam; Rosenberg, Jens T.; Ji, Xin; Grant, Samuel C.; Mattoussi, Hedi
    ACS Nano (2012), 6 (1), 389-399CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    We have designed, prepd., and tested a new set of multidentate catechol- and polyethylene glycol (PEG)-derivatized oligomers, OligoPEG-Dopa, as ligands that exhibit strong affinity to iron oxide nanocrystals. The ligands consist of a short poly(acrylic acid) backbone laterally appended with several catechol anchoring groups and several terminally functionalized PEG moieties to promote affinity to aq. media and to allow further coupling to target mols. (bio and others). These multicoordinating PEGylated oligomers were prepd. using a relatively simple chem. strategy based on N,N'-dicyclohexylcarbodiimide (DCC) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) condensation. The ability of these catechol-functionalized oligomers to impart long-term colloidal stability to the nanoparticles is compared to other control ligands, namely, oligomers presenting several carboxyl groups and monodentate ligands presenting either one catechol or one carboxyl group. We found that the OligoPEG-Dopa ligands provide rapid ligand exchange, and the resulting nanoparticles exhibit greatly enhanced colloidal stability over a broad pH range and in the presence of excess electrolytes; stability is notably improved compared to non-catechol presenting mol. or oligomer ligands. By inserting controllable fractions of azide-terminated PEG moieties, the nanoparticles (NPs) become reactive to complementary functionalities via azide-alkyne cycloaddn. (Click), which opens up the possibility of biol. targeting of such stable NPs. In particular, we tested the Click coupling of azide-functionalized nanoparticles to an alkyne-modified dye. We also measured the MRI T2 contrast of the OligoPEG-capped Fe3O4 nanoparticles and applied MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay to test the potential cytotoxicity of these NPs to live cells; we found no measurable toxicity to live cells.
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    Amstad, E.; Gillich, T.; Bilecka, I.; Textor, M.; Reimhult, E. Ultrastable Iron Oxide Nanoparticle Colloidal Suspensions Using Dispersants with Catechol-Derived Anchor Groups. Nano Lett. 2009, 9, 4042– 4048,  DOI: 10.1021/nl902212q
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    Ultrastable Iron Oxide Nanoparticle Colloidal Suspensions using Dispersants with Catechol-Derived Anchor Groups
    Amstad, Esther; Gillich, Torben; Bilecka, Idalia; Textor, Marcus; Reimhult, Erik
    Nano Letters (2009), 9 (12), 4042-4048CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
    The authors found catechol-deriv. anchor groups which possess irreversible binding affinity to iron oxide and thus can optimally disperse superparamagnetic nanoparticles under physiol. conditions. This not only leads to ultrastable iron oxide nanoparticles but also allows close control over the hydrodynamic diam. and interfacial chem. The latter is a crucial breakthrough to assemble functionalized magnetic nanoparticles, e.g., as targeted magnetic resonance contrast agents.
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    Xiao, W.; Legros, P.; Chevallier, P.; Lagueux, J.; Oh, J. K.; Fortin, M.-A. Superparamagnetic Iron Oxide Nanoparticles Stabilized with Multidentate Block Copolymers for Optimal Vascular Contrast in T 1-Weighted Magnetic Resonance Imaging. ACS Appl. Nano Mater. 2018, 1, 894– 907,  DOI: 10.1021/acsanm.7b00300
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    Superparamagnetic Iron Oxide Nanoparticles Stabilized with Multidentate Block Copolymers for Optimal Vascular Contrast in T1-Weighted Magnetic Resonance Imaging
    Xiao, Wangchuan; Legros, Philippe; Chevallier, Pascale; Lagueux, Jean; Oh, Jung Kwon; Fortin, Marc-Andre
    ACS Applied Nano Materials (2018), 1 (2), 894-907CODEN: AANMF6; ISSN:2574-0970. (American Chemical Society)
    Ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) have been used as vascular contrast agents in magnetic resonance imaging (MRI), mainly for their capacity to generate neg. contrast. To use USPIOs as pos. contrast agents, it is necessary to achieve increased colloidal stability and signal-enhancement performance. Their mol. coatings must be carefully chosen, so that the vascular blood-pool contrast agents lead to long blood turnover times. However, to avoid long-term toxicol. effects, they must also be cleared rapidly through the urinary or gastrointestinal pathways. In this context, highly stable USPIOs showing "pos." contrast in MRI and optimal clearance rates call for the development of robust biocompatible mol. coatings. USPIOs were stabilized with a multidentate block copolymer (MDBC), using a one-pot polyol synthesis method in the presence of a MDBC. Two types of MDBCs having pendant COOH groups in the anchoring block were developed: a polymer with linear-poly(ethylene glycol) (PEG) blocks and a polymer contg. brushed-PEG blocks. The synthesized superparamagnetic Fe3O4 crystals were uniform (5-8 nm in diam.), showed ultrasmall hydrodynamic diams. in dynamic light scattering, and were stable in physiol. liqs. MDBC-coated USPIOs were analyzed in relaxometry, and the formulations showing the strongest potential for T1-weighted vascular imaging (r2/r1: ∼4) were selected for in vivo MRI. Intravascular injections performed in the mouse model indicated long blood retention times and high signal enhancement in MRI for nanoparticles coated with linear-PEG block coatings. Also MDBC/USPIOs could be used in vascular MRI applications, where the nanoparticles must transit the blood for several hours, followed by an efficient clearance in the next days following injection. The use of MDBCs as nanoparticle coatings could open new possibilities in the design of USPIOs for targeted mol. MRI.
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    Wang, W.; Ji, X.; Na, H. B.; Safi, M.; Smith, A.; Palui, G.; Perez, J. M.; Mattoussi, H. Design of a Multi-Dopamine-Modified Polymer Ligand Optimally Suited for Interfacing Magnetic Nanoparticles with Biological Systems. Langmuir 2014, 30, 6197– 6208,  DOI: 10.1021/la500974r
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    Design of a Multi-Dopamine-Modified Polymer Ligand Optimally Suited for Interfacing Magnetic Nanoparticles with Biological Systems
    Wang, Wentao; Ji, Xin; Na, Hyon Bin; Safi, Malak; Smith, Alexandra; Palui, Goutam; Perez, J. Manuel; Mattoussi, Hedi
    Langmuir (2014), 30 (21), 6197-6208CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
    We have designed a set of multifunctional and multicoordinating polymer ligands that are optimally suited for surface functionalizing iron oxide and potentially other magnetic nanoparticles (NPs) and promoting their integration into biol. systems. The amphiphilic polymers are prepd. by coupling (via nucleophilic addn.) several amine-terminated dopamine anchoring groups, poly(ethylene glycol) moieties, and reactive groups onto a poly(isobutylene-alt-maleic anhydride) (PIMA) chain. This design greatly benefits from the highly efficient and reagent-free one-step reaction of maleic anhydride groups with amine-contg. mols. The availability of several dopamine groups in the same ligand greatly enhances the ligand affinity, via multiple coordination, to the magnetic NPs, while the hydrophilic and reactive groups promote colloidal stability in buffer media and allow subsequent conjugation with target biomols. Iron oxide nanoparticles ligand exchanged with these polymer ligands have a compact hydrodynamic size and exhibit enhanced long-term colloidal stability over the pH range of 4-12 and in the presence of excess electrolytes. Nanoparticles ligated with terminally reactive polymers have been easily coupled to target dyes and tested in live cell imaging with no measurable cytotoxicity. Finally, the resulting hydrophilic nanoparticles exhibit large and size-dependent r2 relaxivity values.
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    Wang, W.; Mattoussi, H. Engineering the Bio–Nano Interface Using a Multifunctional Coordinating Polymer Coating. Acc. Chem. Res. 2020, 53, 1124– 1138,  DOI: 10.1021/acs.accounts.9b00641
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    Engineering the Bio-Nano Interface Using a Multifunctional Coordinating Polymer Coating
    Wang, Wentao; Mattoussi, Hedi
    Accounts of Chemical Research (2020), 53 (6), 1124-1138CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
    A review. Conspectus: In the past three decades, interest in using nanoparticles as diagnostic tools to interrogate various biosystems has witnessed remarkable growth. For instance, it has been shown that nanoparticle probes enable the study of cellular processes at the single mol. level. These advances provide new opportunities for understanding fundamental problems in biol., innovation in medicine, and the treatment of diseases. A multitude of nanoparticles have been designed to facilitate in vitro or in vivo sensing, imaging, and diagnostics. Some of those nanoparticle platforms are currently in clin. trials or have been approved by the U.S. Food and Drug Administration. Nonetheless, using nanoparticles in biol. is still facing several obstacles, such as poor colloidal stability under physiol. conditions, nonspecific interactions with serum proteins, and low targeting efficiency in biol. fluids, in addn. to issues of uncontrolled biodistribution and cytotoxicity. All these problems are primarily controlled by the surface stabilizing coating used. In this Account, we summarize recent progress made in our lab. focused on the development of multifunctional polymers as coordinating ligands, to tailor the surface properties of nanoparticles and facilitate their application in biol. We first detail the advantageous features of the coating strategy, followed by a discussion of the key parameters in the ligand design. We then describe the synthesis and use of a series of multicoordinating polymers as ligands optimized for coating quantum dots (QDs), gold nanoparticles (AuNPs), and magnetic nanoparticles (MNPs), with a focus on (i) how to improve the colloidal stability and antifouling performance of materials in biol. conditions; (ii) how to design highly compact coating, without compromising colloidal stability; and (iii) how to tailor the surface functionalities to achieve conjugation to target biomols. We also highlight the ability of a phase transfer strategy, mediated by UV irradn., to promote rapid ligand exchange while preserving the integrity of key functional groups. We then summarize the bioconjugation approaches applied to polymer-coated nanoparticles, with emphasis on the ability of metal-histidine self-assembly and click chem., to control the final nanoparticle bioconjugates. Finally, we demonstrate the use of polymer-coated nanoparticles for sensor design based on redox-active interactions and peptide-mediated intracellular delivery. We anticipate that the coating design presented in this Account would advance the integration of nanoparticles into biol. and medicine.
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    Mai, B. T.; Barthel, M. J.; Lak, A.; Avellini, T.; Panaite, A. M.; Rodrigues, E. M.; Goldoni, L.; Pellegrino, T. Photo-Induced Copper Mediated Copolymerization of Activated-Ester Methacrylate Polymers and Their Use as Reactive Precursors to Prepare Multi-Dentate Ligands for the Water Transfer of Inorganic Nanoparticles. Polym. Chem. 2020, 11, 2969– 2985,  DOI: 10.1039/D0PY00212G
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    Photo-induced copper mediated copolymerization of activated-ester methacrylate polymers and their use as reactive precursors to prepare multi-dentate ligands for the water transfer of inorganic nanoparticles
    Mai, Binh T.; Barthel, Markus J.; Lak, Aidin; Avellini, Tommaso; Panaite, Ana Maria; Rodrigues, Emille M.; Goldoni, Luca; Pellegrino, Teresa
    Polymer Chemistry (2020), 11 (17), 2969-2985CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)
    Multi-dentate ligands enabling a quick and high yield water transfer of inorg. nanocrystals (NCs) via a ligand exchange process is of great interest to promote the applications of NCs in the biomedical field. Here, we describe a facile two-step protocol for the synthesis of polymeric multi-dentate ligands that are suitable for the water transfer of hydrophobic colloidal inorg. nanocrystals (NCs). This protocol first exploits the photo-induced atom transfer radical (photo-ATRP) copolymn. of ester-activated N-succinimidyl methacrylate and oligoethylene glycol Me ether methacrylate. A high monomer conversion rate along with a fair control over the polymn. is confirmed by size exclusion chromatog. and NMR spectroscopy. In the second step, the activated carboxyl moieties of the copolymers are reacted with nucleophilic agents such as 2-aminoethylphosphonic acid or histamine dihydrochloride via a post-polymn. reaction to generate phosphonic- or amino-based multi-dentate ligands, resp. As shown here, polymers comprising poly-phosphonic acid moieties are suitable as multi-dentate ligands for water transfer of multiple varieties of NCs with distinct compns. including iron oxide nanoparticles, CdSe@CdS quantum dots (QDs) and up-converting nanoparticles (UCNPs). Meanwhile the polymers contg. histamine groups are also able to strongly coordinate to the surface of semiconductor QDs, thus enabling their water transfer. Notably, the NCs exhibit long-term stability in physiol. media (saline) upon water transfer, while their size, shape, magnetic properties, and optical properties were also maintained. The UCNPs could be imaged when excited under an IR laser while the QDs show a bright fluorescence signal under UV irradn. QDs coated with a poly-phosphonic acid-based ligand resulted in a more homogeneous coating as demonstrated by the narrow band on gel electrophoresis, along with a higher quantum yield (QY ~ 48%) in comparison with the polyimidazole-based ones (QY ~ 31%). The aq. IONPs instead were proven to provide a transversal relaxation making them useful as contrast agents in magnetic resonance imaging. The water transfer procedure is straightforward thanks to the full soly. of the amphiphilic polymer in the NC chloroform soln. This enables the right interaction between the anchoring moieties on the polymer chains and the surface of NCs, thus replacing the surfactant mols. The gram scale prodn. of the polymer together with the very simple steps of the water transfer protocol enables a quick translation of the protocol for large scale prodn. of aq. stabilized nanoparticles.
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    Cabrera, D.; Lak, A.; Yoshida, T.; Materia, M.; Ortega, D.; Ludwig, F.; Guardia, P.; Sathya, A.; Pellegrino, T.; Teran, F. Unraveling Viscosity Effects on the Hysteresis Losses of Magnetic Nanocubes. Nanoscale 2017, 9, 5094– 5101,  DOI: 10.1039/C7NR00810D
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    Unraveling viscosity effects on the hysteresis losses of magnetic nanocubes
    Cabrera, D.; Lak, A.; Yoshida, T.; Materia, M. E.; Ortega, D.; Ludwig, F.; Guardia, P.; Sathya, A.; Pellegrino, T.; Teran, F. J.
    Nanoscale (2017), 9 (16), 5094-5101CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
    Hysteresis losses in magnetic nanoparticles constitute the basis of magnetic hyperthermia for delivering a local thermal stress. Nevertheless, this therapeutic modality is only to be realized through a careful appraisal of the best possible intrinsic and extrinsic conditions to the nanoparticles for which they maximize and preserve their heating capabilities. Low frequency (100 kHz) hysteresis loops accurately probe the dynamical magnetic response of magnetic nanoparticles in a more reliable manner than calorimetry measurements, providing conclusive quant. data under different exptl. conditions. We consider here a set of iron oxide or cobalt ferrite nanocubes of different sizes, through which we exptl. and theor. study the influence of the viscosity of the medium on the low frequency hysteresis loops of magnetic colloids, and hence their ability to produce and dissipate heat to the surroundings. We analyze the role of nanoparticle size, size distribution, chem. compn., and field intensity in making the magnetization dynamics sensitive to viscosity. Numerical simulations using the stochastic Landau-Lifshitz-Gilbert equation model the exptl. observations in excellent agreement. These results represent an important contribution towards predicting viscosity effects and hence to maximize heat dissipation from magnetic nanoparticles regardless of the environment.
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    Das, R.; Alonso, J.; Nemati Porshokouh, Z.; Kalappattil, V.; Torres, D.; Phan, M.-H.; Garaio, E.; García, J. A. N.; Sanchez Llamazares, J. L.; Srikanth, H. Tunable High Aspect Ratio Iron Oxide Nanorods for Enhanced Hyperthermia. J. Phys. Chem. C 2016, 120, 10086– 10093,  DOI: 10.1021/acs.jpcc.6b02006
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    Tunable High Aspect Ratio Iron Oxide Nanorods for Enhanced Hyperthermia
    Das, Raja; Alonso, Javier; Nemati Porshokouh, Zohreh; Kalappattil, Vijaysankar; Torres, David; Phan, Manh-Huong; Garaio, Eneko; Garcia, Jose Angel; Sanchez Llamazares, Jose Luis; Srikanth, Hariharan
    Journal of Physical Chemistry C (2016), 120 (18), 10086-10093CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
    Despite magnetic hyperthermia being considered one of the most promising techniques for cancer treatment, until now spherical magnetite (Fe3O4) or maghemite (γ-Fe2O3) nanoparticles, which are the most commonly employed and only FDA approved materials, yield the limited heating capacity. Therefore, there is an increasing need for new strategies to improve the heating efficiency or the specific absorption rate (SAR) of these nanosystems. Recently, a large improvement in SAR has been reported for nanocubes of Fe3O4 relative to their spherical counterpart, as a result of their enhanced surface anisotropy and chainlike particle formation. Considering the proven advantages of high aspect ratio one-dimensional (1D) Fe3O4 nanostructures over their spherical and cubic counterparts, such as larger surface area, multisegmented capabilities, enhanced blood circulation time, and prolonged retention in tumors, we propose a novel approach that utilizes this 1D nanostructure for enhanced hyperthermia. Here, we demonstrate that the SAR of iron oxide nanostructures can be enhanced and tuned by altering their aspect ratio. Calorimetric and ac magnetometry expts. performed for the first time on highly cryst. Fe3O4 nanorods consistently show large SAR values (862 W/g for an ac field of 800 Oe), which are superior to spherical and cubic nanoparticles of similar vol. (∼140 and ∼314 W/g, resp.). Increasing the aspect ratio of the nanorods from 6 to 11 improves the SAR by 1.5 times. The nanorods are rapidly aligned by the applied ac field, which appreciably increases the SAR values. A detailed anal. of the effect of the alignment of the nanorods in agar indicates an appreciable SAR increase up to 30% when the nanorods are parallel to the field. These findings pave a new pathway for the design of novel high-aspect ratio magnetic nanostructures for advanced hyperthermia.
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    The biodegradation pathway of triethylamine and its biodegradation by immobilized Arthrobacter protophormiae cells
    Cai, Tianming; Chen, Liwei; Ren, Qian; Cai, Shu; Zhang, Jin
    Journal of Hazardous Materials (2011), 186 (1), 59-66CODEN: JHMAD9; ISSN:0304-3894. (Elsevier B.V.)
    A bacterial strain named R4 was isolated from a wastewater treatment tank contg. triethylamine (TEA) as the sole source of C and N. Strain R4 was identified as Arthrobacter protophormiae based on 16S rRNA gene sequence anal. and morphol. and physiol. properties. The optimal pH, temp. and concn. of NaCl for TEA degrdn. by strain R4 were 7.0, 30° and 0.5%, resp. Strain R4 could completely degrade 100 mg/L TEA to ammonia in 32 h, and could also effectively degrade diethylamine (DEA) and ethylamine (EA) to ammonia. The degrdn. of TEA was strongly inhibited by Cu2+, Mn2+, Zn2+, Co2+, Ni2+ and Ag+ (1.0mM). Addn. of either SO42- or NH4+ reduced the degrdn. efficiency of TEA by strain R4 to a certain extent. The inhibition became significant when the concn. of SO42- and NH4+ reached 11mM and 30 mM, resp. Cell-free exts. prepd. from cells grown in TEA exhibited TEA monooxygenase, DEA monooxygenase and EA monooxygenase activity. We propose the metabolic pathway of TEA degrdn. in strain R4. The efficiency of TEA removal by immobilized cells of strain R4 was equiv. to that of free cells. The immobilized cells could be reused without redn. in their ability to degrade TEA.
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    Lak, A.; Cassani, M.; Mai, B. T.; Winckelmans, N.; Cabrera, D.; Sadrollahi, E.; Marras, S.; Remmer, H.; Fiorito, S.; Cremades-Jimeno, L.; Litterst, F. J.; Ludwig, F.; Manna, L.; Teran, F. J.; Bals, S.; Pellegrino, T. Fe2+ Deficiencies, Feo Subdomains, and Structural Defects Favor Magnetic Hyperthermia Performance of Iron Oxide Nanocubes into Intracellular Environment. Nano Lett. 2018, 18, 6856– 6866,  DOI: 10.1021/acs.nanolett.8b02722
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    Fe2+ Deficiencies, FeO Subdomains, and Structural Defects Favor Magnetic Hyperthermia Performance of Iron Oxide Nanocubes into Intracellular Environment
    Lak, Aidin; Cassani, Marco; Mai, Binh T.; Winckelmans, Naomi; Cabrera, David; Sadrollahi, Elaheh; Marras, Sergio; Remmer, Hilke; Fiorito, Sergio; Cremades-Jimeno, Lucia; Litterst, Fred Jochen; Ludwig, Frank; Manna, Liberato; Teran, Francisco J.; Bals, Sara; Pellegrino, Teresa
    Nano Letters (2018), 18 (11), 6856-6866CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
    Herein, by studying a stepwise phase transformation of 23 nm FeO-Fe3O4 core-shell nanocubes into Fe3O4, we identify a compn. at which the magnetic heating performance of the nanocubes is not affected by the medium viscosity and aggregation. Structural and magnetic characterizations reveal the transformation of the FeO-Fe3O4 nanocubes from having stoichiometric phase compns. into Fe2+-deficient Fe3O4 phases. The resultant nanocubes contain tiny compressed and randomly distributed FeO subdomains as well as structural defects. This phase transformation causes a 10-fold increase in the magnetic losses of the nanocubes, which remain exceptionally insensitive to the medium viscosity as well as aggregation unlike similarly sized single-phase magnetite nanocubes. We observe that the dominant relaxation mechanism switches from N´eel in fresh core-shell nanocubes to Brownian in partially oxidized nanocubes and once again to N´eel in completely treated nanocubes. The Fe2+ deficiencies and structural defects appear to reduce the magnetic energy barrier and anisotropy field, thereby driving the overall relaxation into N´eel process. The magnetic losses of these nanoparticles remain unchanged through a progressive internalization/assocn. to ovarian cancer cells. Moreover, the particles induce a significant cell death after being exposed to hyperthermia treatment. Here, we present the largest heating performance that has been reported to date for 23 nm iron oxide nanoparticles under intracellular conditions. Our findings clearly demonstrate the pos. impacts of the Fe2+ deficiencies and structural defects in the Fe3O4 structure on the heating performance into intracellular environment.
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    Serantes, D.; Simeonidis, K.; Angelakeris, M.; Chubykalo-Fesenko, O.; Marciello, M.; Morales, M. D. P.; Baldomir, D.; Martinez-Boubeta, C. Multiplying Magnetic Hyperthermia Response by Nanoparticle Assembling. J. Phys. Chem. C 2014, 118, 5927– 5934,  DOI: 10.1021/jp410717m
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    Multiplying Magnetic Hyperthermia Response by Nanoparticle Assembling
    Serantes, David; Simeonidis, Konstantinos; Angelakeris, Makis; Chubykalo-Fesenko, Oksana; Marciello, Marzia; Morales, Maria del Puerto; Baldomir, Daniel; Martinez-Boubeta, Carlos
    Journal of Physical Chemistry C (2014), 118 (11), 5927-5934CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
    The oriented attachment of magnetic nanoparticles is recognized as an important pathway in the magnetic-hyperthermia cancer treatment roadmap, thus, understanding the phys. origin of their enhanced heating properties is a crucial task for the development of optimized application schemes. Here, we present a detailed theor. anal. of the hysteresis losses in dipolar-coupled magnetic nanoparticle assemblies as a function of both the geometry and length of the array, and of the orientation of the particles' magnetic anisotropy. Our results suggest that the chain-like arrangement biomimicking magnetotactic bacteria has the superior heating performance, increasing more than 5 times in comparison with the randomly distributed system when aligned with the magnetic field. The size of the chains and the anisotropy of the particles can be correlated with the applied magnetic field in order to have optimum conditions for heat dissipation. Our exptl. calorimetrical measurements performed in aq. and agar gel suspensions of 44 nm magnetite nanoparticles at different densities, and oriented in a magnetic field, unambiguously demonstrate the important role of chain alignment on the heating efficiency. In low agar viscosity, similar to those of common biol. media, the initial orientation of the chains plays a minor role in the enhanced heating capacity while at high agar viscosity, chains aligned along the applied magnetic field show the max. heating. This knowledge opens new perspectives for improved handling of magnetic hyperthermia agents, an alternative to conventional cancer therapies.
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    The relevance of Brownian relaxation as power absorption mechanism in Magnetic Hyperthermia
    Torres Teobaldo E; Calatayud M Pilar; Sanz Beatriz; Ibarra Alfonso; Fernandez-Pacheco Rodrigo; Ibarra M Ricardo; Goya Gerardo F; Torres Teobaldo E; Ibarra Alfonso; Fernandez-Pacheco Rodrigo; Ibarra M Ricardo; Lima Enio Jr; Mayoral Alvaro; Marquina Clara; Ibarra M Ricardo; Goya Gerardo F; Marquina Clara
    Scientific reports (2019), 9 (1), 3992 ISSN:.
    The Linear Response Theory (LRT) is a widely accepted framework to analyze the power absorption of magnetic nanoparticles for magnetic fluid hyperthermia. Its validity is restricted to low applied fields and/or to highly anisotropic magnetic nanoparticles. Here, we present a systematic experimental analysis and numerical calculations of the specific power absorption for highly anisotropic cobalt ferrite (CoFe2O4) magnetic nanoparticles with different average sizes and in different viscous media. The predominance of Brownian relaxation as the origin of the magnetic losses in these particles is established, and the changes of the Specific Power Absorption (SPA) with the viscosity of the carrier liquid are consistent with the LRT approximation. The impact of viscosity on SPA is relevant for the design of MNPs to heat the intracellular medium during in vitro and in vivo experiments. The combined numerical and experimental analyses presented here shed light on the underlying mechanisms that make highly anisotropic MNPs unsuitable for magnetic hyperthermia.
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    The era of chemotherapy began in the 1940s with the first uses of nitrogen mustards and antifolate drugs. Cancer drug development since then has transformed from a low-budget, government-supported research effort to a high-stakes, multi-billion dollar industry. The targeted-therapy revolution has arrived, but the principles and limitations of chemotherapy discovered by the early researchers still apply. This article chronicles the history of modern chemotherapy and identifies remaining challenges for the next generation of researchers.
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  • Abstract

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    Figure 1

    Figure 1. Characterization of multidentate and functional polymers by 1H NMR. 1H NMR spectra (with the assignments of the characteristic peaks) of P(PEGMA-co-NSMA) (A); polymer precursor upon the reaction with NH2-PEG-N3, furfurylamine, and dopamine hydrochloride (PEG-CF-N3) (B); and multifunctional PEGylated polymeric ligand (PEG-CDoxo-N3) after the reaction between PEG-CF-N3 and maleimide-derived doxorubicin (C); and (D) multifunctional PEGylated polymeric ligand (PEG-CFluo-COOH) after the reaction between PEG-CF-COOH and maleimide-derived fluorescein. The measurements were done using deuterated DMSO as the solvent.

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    Scheme 1

    Scheme 1. Representative Synthetic Approach To Prepare Multifunctional PEGylated Polymeric Ligands Using Activated Ester Methacrylate-Based Polymers and Diels–Alder Click Chemistry
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    aPoly(polyethylene glycol methacrylate-co-N-succinimidyl methacrylate), P(PEGMA-co-NSMA), is used as a reactive precursor to introduce functional PEG, catechol, and furfuryl pendants by means of a one-pot aminolysis reaction, followed by the conjugation of biomolecules such as maleimide-derived fluorescein (Fluo) or maleimide-derived doxorubicin (Doxo) by Diels–Alder click chemistry.

    Figure 2

    Figure 2. Phase transfer of iron oxide nanocubes (IONCs) using a two-step ligand exchange. (A) Sketch represents the two-step phase transfer procedure involving first the transfer of IONCs from chloroform into water using tetramethylammonium hydroxide (TMAOH), followed by the postexchange in water of TMAOH with the developed ligands in basic solution, to yield physiologically stable IONCs. The dye/drug conjugated to the ligand platform via a thermal labile Diels–Alder adduct could be released by the local heat generated on the nanocube surface during MHT, as illustrated in the inset. FT-IR spectra of surface modification of IONCs for each step of the water transfer protocol (B) and in the extended region of interest from 1000 to 1900 cm–1 (C). Dynamic light scattering (DLS) traces of water-soluble IONCs modified with TMAOH (green), PEG-CF (blue), PEG-CFluo-COOH (red), and PEG-CDoxo-N3 (deep red) weighted by intensity (D). TEM images of IONCs functionalized with TMAOH (E), or with PEG-CF (F), or with PEG-CFluo-COOH (G), or with PEG-CDoxo-N3 (H) deposited from water.

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    Figure 3

    Figure 3. Stability of IONCs functionalized with multidentate and functional polymer ligands in physiological conditions. DLS traces of IONCs modified with PEG-CDoxo-N3 (A) or with PEG-CF-N3 (B) dispersed in complete cell culture media at 10% fetal bovine serum at day 0 and after 2, 5, and 8 days of storage at ambient conditions. The insets show the vials, as observed under visible light for the culture media (1) and for IONCs modified with either PEG-CDoxo-N3 or PEG-CF-N3 ligands, respectively (2).

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    Figure 4

    Figure 4. Heating capability of IONCs in water and viscous media. (A) Specific absorption rate (SAR) values in water of IONCs having different surface ligands. (B,C) Comparison of the SAR value of IONCs functionalized with PEG-CFluo-COOH in water and viscous media (glycerol 81%) measured under the MHT conditions with respect to the biological limit (H·f < 5 × 109 A·m–1·s–1). The values reported in panel 4B were measured at 110 kHz, with the field varied from 16 to 40 kA·m–1.

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    Figure 5

    Figure 5. Release of dye molecules by means of MHT-induced local (hot-spot) heat effect. Heating profiles of IONC-PEG-CDoxo-N3 (A) and IONC-PEG-CFluo-COOH (D) solution in water at different Fe concentrations (0.5 and 1.0 g/L) and control solution (only water) under MHT (16 kA·m–1 and 110 kHz) during the first 10 min of MHT. We observed that the maximum temperature was reached after 10 min; thus, further heating profiles are not shown. The comparison of the PL signal of Doxo (B) and fluorescein sodium salt (E) between the samples kept on bench and the one undergoing MHT (110 kHz, 16 kA·m–1) at the Fe concentration of 0.5 gFe/L (at different durations of MHT). The normalized concentration of Doxo (C) and fluorescein sodium salt (F) released upon MHT (16 kA·m–1 and 110 kHz) at Fe concentrations of 0.5 gFe/L.

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      A review.
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    4. 4
      Mai, B. T.; Fernandes, S.; Balakrishnan, P. B.; Pellegrino, T. Nanosystems Based on Magnetic Nanoparticles and Thermo-or Ph-Responsive Polymers: An Update and Future Perspectives. Acc. Chem. Res. 2018, 51, 999– 1013,  DOI: 10.1021/acs.accounts.7b00549
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      Nanosystems Based on Magnetic Nanoparticles and Thermo- or pH-Responsive Polymers: An Update and Future Perspectives
      Mai, Binh T.; Fernandes, Soraia; Balakrishnan, Preethi B.; Pellegrino, Teresa
      Accounts of Chemical Research (2018), 51 (5), 999-1013CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
      A review. The combination of hard matter, like magnetic nanoparticles (MNPs) and soft materials, like polymers, can generate multi-purpose materials with a broad range of applications. Here, the merging of unique features of MNPs with peculiar polymer responsiveness properties, such as pH and thermo-stimuli activation, enable the smart control of polymer properties operated by the magnetic nanoparticles and vice versa, at a level of unprecedented sophistication. These magnetic-stimuli-responsive nanosystems have impacted the medical research with evidences for controlled drug delivery and for tracking the drug release; for combining magnetic hyperthermia and stimuli-dependent drug delivery, and for diagnosis pathol. conditions (such as pH-changes at ischemic site). Despite great efforts by chemists to fabricate different featured materials, proof of concepts are widely demonstrated in vitro in test tubes and in cell studies but successfully preclin. studies are only few. A clin. translation of magnetic stimuli-responsive systems would require overcoming the actual nanosystem limitations and the joint efforts of an interdisciplinary scientific community. By framing state of the art of magnetic-stimuli-responsive systems following an organization based on the response mechanisms of polymers, challenges to overcome and future directions are suggested in this perspective.
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    5. 5
      Cardoso, V. F.; Francesko, A.; Ribeiro, C.; Bañobre-López, M.; Martins, P.; Lanceros-Mendez, S. Advances in Magnetic Nanoparticles for Biomedical Applications. Adv. Healthcare Mater. 2018, 7, 1700845  DOI: 10.1002/adhm.201700845
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      Chang, D.; Lim, M.; Goos, J. A.; Qiao, R.; Ng, Y. Y.; Mansfeld, F. M.; Jackson, M.; Davis, T. P.; Kavallaris, M. Biologically Targeted Magnetic Hyperthermia: Potential and Limitations. Front. Pharmacol. 2018, 9, 831,  DOI: 10.3389/fphar.2018.00831
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      Biologically targeted magnetic hyperthermia: potential and limitations
      Chang, David; Lim, May; Goos, Jeroen A. C. M.; Qiao, Ruirui; Ng, Yun Yee; Mansfeld, Friederike M.; Jackson, Michael; Davis, Thomas P.; Kavallaris, Maria
      Frontiers in Pharmacology (2018), 9 (), 831/1-831/20CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)
      Hyperthermia, the mild elevation of temp. to 40-43°C, can induce cancer cell death and enhance the effects of radiotherapy and chemotherapy. However, achievement of its full potential as a clin. relevant treatment modality has been restricted by its inability to effectively and preferentially heat malignant cells. The limited spatial resoln. may be circumvented by the i.v. administration of cancer-targeting magnetic nanoparticles that accumulate in the tumor, followed by the application of an alternating magnetic field to raise the temp. of the nanoparticles located in the tumor tissue. This targeted approach enables preferential heating of malignant cancer cells while sparing the surrounding normal tissue, potentially improving the effectiveness and safety of hyperthermia. Despite promising results in preclin. studies, there are numerous challenges that must be addressed before this technique can progress to the clinic. This review discusses these challenges and highlights the current understanding of targeted magnetic hyperthermia.
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    7. 7
      Chandrasekharan, P.; Tay, Z. W.; Hensley, D.; Zhou, X. Y.; Fung, B. K.; Colson, C.; Lu, Y.; Fellows, B. D.; Huynh, Q.; Saayujya, C.; Yu, E.; Orendorff, R.; Zheng, B.; Goodwill, P.; Rinaldi, C.; Conolly, S. Using Magnetic Particle Imaging Systems to Localize and Guide Magnetic Hyperthermia Treatment: Tracers, Hardware, and Future Medical Applications. Theranostics 2020, 10, 2965,  DOI: 10.7150/thno.40858
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      7
      Using magnetic particle imaging systems to localize and guide magnetic hyperthermia treatment: tracers, hardware, and future medical applications
      Chandrasekharan, Prashant; Tay, Zhi Wei; Hensley, Daniel; Zhou, Xinyi Y.; Fung, Barry K. L.; Colson, Caylin; Lu, Yao; Fellows, Benjamin D.; Huynh, Quincy; Saayujya, Chinmoy; Yu, Elaine; Orendorff, Ryan; Zheng, Bo; Goodwill, Patrick; Rinaldi, Carlos; Conolly, Steven
      Theranostics (2020), 10 (7), 2965-2981CODEN: THERDS; ISSN:1838-7640. (Ivyspring International Publisher)
      A review. Magnetic fluid hyperthermia (MFH) treatment makes use of a suspension of superparamagnetic iron oxide nanoparticles, administered systemically or locally, in combination with an externally applied alternating magnetic field, to ablate target tissue by generating heat through a process called induction. The heat generated above the mammalian euthermic temp. of 37°C induces apoptotic cell death and/or enhances the susceptibility of the target tissue to other therapies such as radiation and chemotherapy. While most hyperthermia techniques currently in development are targeted towards cancer treatment, hyperthermia is also used to treat restenosis, to remove plaques, to ablate nerves and to alleviate pain by increasing regional blood flow. While RF hyperthermia can be directed invasively towards the site of treatment, non-invasive localization of heat through induction is challenging. In this review, we discuss recent progress in the field of RF magnetic fluid hyperthermia and introduce a new diagnostic imaging modality called magnetic particle imaging that allows for a focused theranostic approach encompassing treatment planning, treatment monitoring and spatially localized inductive heating.
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    8. 8
      Gavilán, H.; Avugadda, S. K.; Fernández-Cabada, T.; Soni, N.; Cassani, M.; Mai, B. T.; Chantrell, R.; Pellegrino, T. Magnetic Nanoparticles and Clusters for Magnetic Hyperthermia: Optimizing Their Heat Performance and Developing Combinatorial Therapies to Tackle Cancer. Chem. Soc. Rev. 2021, 50, 11614– 11667,  DOI: 10.1039/D1CS00427A
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      8
      Magnetic nanoparticles and clusters for magnetic hyperthermia: optimizing their heat performance and developing combinatorial therapies to tackle cancer
      Gavilan, Helena; Avugadda, Sahitya Kumar; Fernandez-Cabada, Tamara; Soni, Nisarg; Cassani, Marco; Mai, Binh T.; Chantrell, Roy; Pellegrino, Teresa
      Chemical Society Reviews (2021), 50 (20), 11614-11667CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. Magnetic hyperthermia (MHT) is a therapeutic modality for the treatment of solid tumors that has now accumulated more than 30 years of experience. In the ongoing MHT clin. trials for the treatment of brain and prostate tumors, iron oxide nanoparticles are employed as intra-tumoral MHT agents under a patient-safe 100 kHz alternating magnetic field (AMF) applicator. Although iron oxide nanoparticles are currently approved by FDA for imaging purposes and for the treatment of anemia, magnetic nanoparticles (MNPs) designed for the efficient treatment of MHT must respond to specific phys.-chem. properties in terms of magneto-energy conversion, heat dose prodn., surface chem. and aggregation state. Accordingly, in the past few decades, these requirements have boosted the development of a new generation of MNPs specifically aimed for MHT. In this review, we present an overview on MNPs and their assemblies produced via different synthetic routes, focusing on which MNP features have allowed unprecedented heating efficiency levels to be achieved in MHT and highlighting nanoplatforms that prevent magnetic heat loss in the intracellular environment. Moreover, we review the advances on MNP-based nanoplatforms that embrace the concept of multimodal therapy, which aims to combine MHT with chemotherapy, radiotherapy, immunotherapy, photodynamic or phototherapy. Next, for a better control of the therapeutic temp. at the tumor, we focus on the studies that have optimized MNPs to maintain gold-std. MHT performance and are also tackling MNP imaging with the aim to quant. assess the amt. of nanoparticles accumulated at the tumor site and regulate the MHT field conditions. To conclude, future perspectives with guidance on how to advance MHT therapy will be provided.
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    9. 9
      Cazares-Cortes, E.; Cabana, S.; Boitard, C.; Nehlig, E.; Griffete, N.; Fresnais, J.; Wilhelm, C.; Abou-Hassan, A.; Ménager, C. Recent Insights in Magnetic Hyperthermia: From the “Hot-Spot” Effect for Local Delivery to Combined Magneto-Photo-Thermia Using Magneto-Plasmonic Hybrids. Adv. Drug Delivery Rev. 2019, 138, 233– 246,  DOI: 10.1016/j.addr.2018.10.016
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      9
      Recent insights in magnetic hyperthermia: From the "hot-spot" effect for local delivery to combined magneto-photo-thermia using magneto-plasmonic hybrids
      Cazares-Cortes, Esther; Cabana, Sonia; Boitard, Charlotte; Nehlig, Emilie; Griffete, Nebewia; Fresnais, Jerome; Wilhelm, Claire; Abou-Hassan, Ali; Menager, Christine
      Advanced Drug Delivery Reviews (2019), 138 (), 233-246CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)
      A review. Magnetic hyperthermia which exploits the heat generated by magnetic nanoparticles (MNPs) when exposed to an alternative magnetic field (AMF) is now in clin. trials for the treatment of cancers. However, this thermal therapy requires a high amt. of MNPs in the tumor to be efficient. On the contrary the hot spot local effect refers to the use of specific temp. profile at the vicinity of nanoparticles for heating with minor to no long-range effect. This magneto-thermal effect can be exploited as a relevant external stimulus to temporally and spatially trigger drug release. In this review, we focus on recent advances in magnetic hyperthermia. Indirect exptl. proofs of the local temp. increase are first discussed leading to a good estn. of the temp. at the surface (from 0.5 to 6 nm) of superparamagnetic NPs. Then we highlight recent studies illustrating the hot-spot effect for drug-release. Finally, we present another recent strategy to enhance the efficacity of thermal treatment by combining photothermal therapy with magnetic hyperthermia mediated by magneto-plasmonic nanoplatforms.
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    10. 10
      Mahmoudi, K.; Bouras, A.; Bozec, D.; Ivkov, R.; Hadjipanayis, C. Magnetic Hyperthermia Therapy for the Treatment of Glioblastoma: A Review of the Therapy’s History, Efficacy and Application in Humans. Int. J. Hyperthermia 2018, 34, 1316– 1328,  DOI: 10.1080/02656736.2018.1430867
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      10
      Magnetic hyperthermia therapy for the treatment of glioblastoma: a review of the therapy's history, efficacy and application in humans
      Mahmoudi Keon; Bouras Alexandros; Bozec Dominique; Hadjipanayis Constantinos; Ivkov Robert; Hadjipanayis Constantinos
      International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group (2018), 34 (8), 1316-1328 ISSN:.
      Hyperthermia therapy (HT) is the exposure of a region of the body to elevated temperatures to achieve a therapeutic effect. HT anticancer properties and its potential as a cancer treatment have been studied for decades. Techniques used to achieve a localised hyperthermic effect include radiofrequency, ultrasound, microwave, laser and magnetic nanoparticles (MNPs). The use of MNPs for therapeutic hyperthermia generation is known as magnetic hyperthermia therapy (MHT) and was first attempted as a cancer therapy in 1957. However, despite more recent advancements, MHT has still not become part of the standard of care for cancer treatment. Certain challenges, such as accurate thermometry within the tumour mass and precise tumour heating, preclude its widespread application as a treatment modality for cancer. MHT is especially attractive for the treatment of glioblastoma (GBM), the most common and aggressive primary brain cancer in adults, which has no cure. In this review, the application of MHT as a therapeutic modality for GBM will be discussed. Its therapeutic efficacy, technical details, and major experimental and clinical findings will be reviewed and analysed. Finally, current limitations, areas of improvement, and future directions will be discussed in depth.
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    11. 11
      Southern, P.; Pankhurst, Q. A. Commentary on the Clinical and Preclinical Dosage Limits of Interstitially Administered Magnetic Fluids for Therapeutic Hyperthermia Based on Current Practice and Efficacy Models. Int. J. Hyperthermia 2018, 34, 671– 686,  DOI: 10.1080/02656736.2017.1365953
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      11
      Commentary on the clinical and preclinical dosage limits of interstitially administered magnetic fluids for therapeutic hyperthermia based on current practice and efficacy models
      Southern, Paul; Pankhurst, Quentin A.
      International Journal of Hyperthermia (2018), 34 (6), 671-686CODEN: IJHYEQ; ISSN:0265-6736. (Taylor & Francis Ltd.)
      We offer a critique of what constitutes a suitable dosage limit, in both clin. and preclin. studies, for interstitially administered magnetic nanoparticles in order to enable therapeutic hyperthermia under the action of an externally applied alternating magnetic field. We approach this first from the perspective of the currently approved clin. dosages of magnetic nanoparticles in the fields of MRI contrast enhancement, sentinel node detection, iron replacement therapy and magnetic thermoablation. We compare this to a simple anal. model of the achievable hyperthermia temp. rise in both humans and animals based on the interstitially administered dose, the heating and dispersion characteristics of the injected fluid, and the strength and frequency of the applied magnetic field. We show that under appropriately chosen conditions a therapeutic temp. rise is achievable in clin. relevant situations. We also show that in such cases it may paradoxically be harder to achieve the same therapeutic temp. rise in a preclin. model. We comment on the implications for the evidence-based translation of hyperthermia based interventions from the lab. to the clinic.
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    12. 12
      Attaluri, A.; Kandala, S. K.; Zhou, H.; Wabler, M.; DeWeese, T. L.; Ivkov, R. Magnetic Nanoparticle Hyperthermia for Treating Locally Advanced Unresectable and Borderline Resectable Pancreatic Cancers: The Role of Tumor Size and Eddy-Current Heating. Int. J. Hyperthermia 2020, 37, 108– 119,  DOI: 10.1080/02656736.2020.1798514
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      12
      Magnetic nanoparticle hyperthermia for treating locally advanced unresectable and borderline resectable pancreatic cancers: the role of tumor size and eddy-current heating
      Attaluri, Anilchandra; Kandala, Sri Kamal; Zhou, Haoming; Wabler, Michele; DeWeese, Theodore L.; Ivkov, Robert
      International Journal of Hyperthermia (2020), 37 (3), 108-119CODEN: IJHYEQ; ISSN:0265-6736. (Taylor & Francis Ltd.)
      Tumor vol. largely dets. the success of local control of borderline resectable and locally advanced pancreatic cancer with current therapy. We hypothesized that a tumor-mass normalized dose of magnetic nanoparticle hyperthermia (MNPH) with alternating magnetic fields (AMFs) reduces the effect of tumor vol. for treatment. 18 female athymic nude mice bearing s.c. MiaPaCa02 human xenograft tumors were treated with MNPH following intratumor injections of 5.5 mg Fe/g tumor of an aq. suspension of magnetic iron-oxide nanoparticles. Mice were randomly divided into control (n = 5) and treated groups having small (0.15 ± 0.03 cm3, n = 4) or large (0.30 ± 0.06 cm3, n = 5) tumors. We assessed the clin. feasibility of this approach and of pulsed AMF to minimize eddy current heating using a finite-element method to solve a bioheat equation for a human-scale multilayer model. Compared to the control group, both small and large MiaPaCa02 s.c. tumors showed statistically significant growth inhibition. Conversely, there was no significant difference in tumor growth between large and small tumors. Both computational and xenograft models demonstrated higher max. tumor temps. for large tumors compared to small tumors. Computational modeling demonstrates that pulsed AMF can minimize nonspecific eddy current heating. MNPH provides an advantage to treat large tumors because the MION dose can be adjusted to increase power. Pulsed AMF, with adjusted treatment time, can enhance MNPH in challenging cases such as low MION dose in the target tissue and/or large patients by minimizing nonspecific eddy current heating without sacrificing thermal dose to the target. Nanoparticle heterogeneity in tumors remains a challenge for continued research.
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    13. 13
      Moros, M.; Idiago-López, J.; Asín, L.; Moreno-Antolín, E.; Beola, L.; Grazú, V.; Fratila, R. M.; Gutiérrez, L.; de la Fuente, J. M. Triggering Antitumoural Drug Release and Gene Expression by Magnetic Hyperthermia. Adv. Drug Delivery Rev. 2019, 138, 326– 343,  DOI: 10.1016/j.addr.2018.10.004
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      13
      Triggering antitumoural drug release and gene expression by magnetic hyperthermia
      Moros, Maria; Idiago-Lopez, Javier; Asin, Laura; Moreno-Antolin, Eduardo; Beola, Lilianne; Grazu, Valeria; Fratila, Raluca M.; Gutierrez, Lucia; de la Fuente, Jesus Martinez
      Advanced Drug Delivery Reviews (2019), 138 (), 326-343CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)
      A review. Magnetic nanoparticles (MNPs) are promising tools for a wide array of biomedical applications. One of their most outstanding properties is the ability to generate heat when exposed to alternating magnetic fields, usually exploited in magnetic hyperthermia therapy of cancer. In this contribution, we provide a crit. of the use of MNPs and magnetic hyperthermia as drug release and gene expression triggers for cancer therapy. Several strategies for the release of chemotherapeutic drugs from thermo-responsive matrixes are discussed, providing representative examples of their application at different levels (from proof of concept to in vivo applications). The potential of magnetic hyperthermia to promote in situ expression of therapeutic genes using vectors that contain heat-responsive promoters is also ed in the context of cancer gene therapy.
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    14. 14
      Mai, B. T.; Balakrishnan, P. B.; Barthel, M. J.; Piccardi, F.; Niculaes, D.; Marinaro, F.; Fernandes, S.; Curcio, A.; Kakwere, H.; Autret, G.; Cingolani, R.; Gazeau, F.; Pellegrino, T. Thermoresponsive Iron Oxide Nanocubes for an Effective Clinical Translation of Magnetic Hyperthermia and Heat-Mediated Chemotherapy. ACS Appl. Mater. Interfaces 2019, 11, 5727– 5739,  DOI: 10.1021/acsami.8b16226
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      14
      Thermoresponsive Iron Oxide Nanocubes for an Effective Clinical Translation of Magnetic Hyperthermia and Heat-Mediated Chemotherapy
      Mai Binh T; Balakrishnan Preethi B; Barthel Markus J; Piccardi Federica; Niculaes Dina; Marinaro Federica; Fernandes Soraia; Curcio Alberto; Kakwere Hamilton; Cingolani Roberto; Pellegrino Teresa; Mai Binh T; Balakrishnan Preethi B; Niculaes Dina; Autret Gwennhael; Gazeau Florence
      ACS applied materials & interfaces (2019), 11 (6), 5727-5739 ISSN:.
      The use of magnetic nanoparticles in oncothermia has been investigated for decades, but an effective combination of magnetic nanoparticles and localized chemotherapy under clinical magnetic hyperthermia (MH) conditions calls for novel platforms. In this study, we have engineered magnetic thermoresponsive iron oxide nanocubes (TR-cubes) to merge MH treatment with heat-mediated drug delivery, having in mind the clinical translation of the nanoplatform. We have chosen iron oxide based nanoparticles with a cubic shape because of their outstanding heat performance under MH clinical conditions, which makes them benchmark agents for MH. Accomplishing a surface-initiated polymerization of strongly interactive nanoparticles such as our iron oxide nanocubes, however, remains the main challenge to overcome. Here, we demonstrate that it is possible to accelerate the growth of a polymer shell on each nanocube by simple irradiation of a copper-mediated polymerization with a ultraviolet light (UV) light, which both speeds up the polymerization and prevents nanocube aggregation. Moreover, we demonstrate herein that these TR-cubes can carry chemotherapeutic doxorubicin (DOXO-loaded-TR-cubes) without compromising their thermoresponsiveness both in vitro and in vivo. In vivo efficacy studies showed complete tumor suppression and the highest survival rate for animals that had been treated with DOXO-loaded-TR-cubes, only when they were exposed to MH. The biodistribution of intravenously injected TR-cubes showed signs of renal clearance within 1 week and complete clearance after 5 months. This biomedical platform works under clinical MH conditions and at a low iron dosage, which will enable the translation of dual MH/heat-mediated chemotherapy, thus overcoming the clinical limitation of MH: i.e., being able to monitor tumor progression post-MH-treatment by magnetic resonance imaging (MRI).
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    15. 15
      Fernandes, S.; Fernandez, T.; Metze, S.; Balakrishnan, P. B.; Mai, B. T.; Conteh, J.; De Mei, C.; Turdo, A.; Di Franco, S.; Stassi, G. Magnetic Nanoparticle-Based Hyperthermia Mediates Drug Delivery and Impairs the Tumorigenic Capacity of Quiescent Colorectal Cancer Stem Cells. ACS Appl. Mater. Interfaces 2021, 13, 15959– 15972,  DOI: 10.1021/acsami.0c21349
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      15
      Magnetic Nanoparticle-Based Hyperthermia Mediates Drug Delivery and Impairs the Tumorigenic Capacity of Quiescent Colorectal Cancer Stem Cells
      Fernandes, Soraia; Fernandez, Tamara; Metze, Sabrina; Balakrishnan, Preethi B.; Mai, Binh T.; Conteh, John; De Mei, Claudia; Turdo, Alice; Di Franco, Simone; Stassi, Giorgio; Todaro, Matilde; Pellegrino, Teresa
      ACS Applied Materials & Interfaces (2021), 13 (14), 15959-15972CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
      Cancer stem cells (CSCs) are the tumor cell subpopulation responsible for resistance to chemotherapy, tumor recurrence, and metastasis. An efficient therapy must act on low proliferating quiescent-CSCs (q-CSCs). We here investigate the effect of magnetic hyperthermia (MHT) in combination with local chemotherapy as a dual therapy to inhibit patient-derived colorectal qCR-CSCs. We apply iron oxide nanocubes as MHT heat mediators, coated with a thermoresponsive polymer (TR-Cubes) and loaded with DOXO (TR-DOXO) as a chemotherapeutic agent. The thermoresponsive polymer releases DOXO only at a temp. above 44°C. In colony-forming assays, the cells exposed to TR-Cubes with MHT reveal that qCR-CSCs struggle to survive the heat damage and, with a due delay, restart the division of dormant cells. The eradication of qCR-CSCs with a complete stop of the colony formation was achieved only with TR-DOXO when exposed to MHT. The in vivo tumor formation study confirms the combined effects of MHT with heat-mediated drug release: only the group of animals that received the CR-CSCs pretreated, in vitro, with TR-DOXO and MHT lacked the formation of tumor even after several months. For DOXO-resistant CR-CSCs cells, the same results were shown, in vitro, when choosing the drug oxaliplatin rather than DOXO and applying MHT. These findings emphasize the potential of our nanoplatforms as an effective patient-personalized cancer treatment against qCR-CSCs.
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    16. 16
      Lee, J. H.; Chen, K. J.; Noh, S. H.; Garcia, M. A.; Wang, H.; Lin, W. Y.; Jeong, H.; Kong, B. J.; Stout, D. B.; Cheon, J. On-Demand Drug Release System for in Vivo Cancer Treatment through Self-Assembled Magnetic Nanoparticles. Angew. Chem., Int. Ed. Engl. 2013, 125, 4480– 4484,  DOI: 10.1002/anie.201207721
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      Guisasola, E.; Baeza, A.; Talelli, M.; Arcos, D.; Moros, M.; de la Fuente, J. M.; Vallet-Regí, M. Magnetic-Responsive Release Controlled by Hot Spot Effect. Langmuir 2015, 31, 12777– 12782,  DOI: 10.1021/acs.langmuir.5b03470
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      Magnetic-Responsive Release Controlled by Hot Spot Effect
      Guisasola, Eduardo; Baeza, Alejandro; Talelli, Marina; Arcos, Daniel; Moros, Maria; de la Fuente, Jesus M.; Vallet-Regi, Maria
      Langmuir (2015), 31 (46), 12777-12782CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
      Magnetically triggered drug delivery nanodevices have attracted great attention in nanomedicine, as they can feature as smart carriers releasing their payload at clinician's will. The key principle of these devices is based on the properties of magnetic cores to generate thermal energy in the presence of an alternating magnetic field. Then, the temp. increase triggers the drug release. Despite this potential, the rapid heat dissipation in living tissues is a serious hindrance for their clin. application. It is hypothesized that magnetic cores could act as hot spots, this is, produce enough heat to trigger the release without the necessity to increase the global temp. Herein, a nanocarrier has been designed to respond when the temp. reaches 43 °C. This material has been able to release its payload under an alternating magnetic field without the need of increasing the global temp. of the environment, proving the efficacy of the hot spot mechanism in magnetic-responsive drug delivery devices.
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      Cazares-Cortes, E.; Nerantzaki, M.; Fresnais, J.; Wilhelm, C.; Griffete, N.; Ménager, C. Magnetic Nanoparticles Create Hot Spots in Polymer Matrix for Controlled Drug Release. Nanomaterials 2018, 8, 850,  DOI: 10.3390/nano8100850
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      18
      Magnetic nanoparticles create hot spots in polymer matrix for controlled drug release
      Cazares-Cortes, Esther; Nerantzaki, Maria; Fresnais, Jerome; Wilhelm, Claire; Griffete, Nebewia; Menager, Christine
      Nanomaterials (2018), 8 (10), 850/1-850/11CODEN: NANOKO; ISSN:2079-4991. (MDPI AG)
      Herein, original magnetic drug delivery nanomaterials for cancer therapy are developed and compared, with the purpose to show active control over drug release by using an alternative magnetic field (AMF). The rationale is to combine polymers and superparamagnetic nanoparticles to trigger such drug release under AMF. Two magnetic nanosystems are thus presented: magnetic nanogels made of thermosensitive and biocompatible polymers and core-shell nanoparticles with a magnetic core and a molecularly imprinted polymer as shell. Both encapsulate doxorubicin (DOX) and the DOX controlled release was investigated in vitro and in cells under AMF excitation. It confirms that the local heat profile at the vicinity of the iron oxide core can be used for the DOX controlled release. It also shows that both nanosystems help delivering more DOX inside the cells compared to internalization of free DOX. Finally, the DOX intracellular release could be remotely triggered under AMF, in athermal conditions, thus enhancing DOX cytotoxicity.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFSjs7%252FL&md5=f1c780ff0674804203e2b0c50b3981bc
    19. 19
      Riedinger, A.; Guardia, P.; Curcio, A.; Garcia, M. A.; Cingolani, R.; Manna, L.; Pellegrino, T. Subnanometer Local Temperature Probing and Remotely Controlled Drug Release Based on Azo-Functionalized Iron Oxide Nanoparticles. Nano Lett. 2013, 13, 2399– 2406,  DOI: 10.1021/nl400188q
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      Subnanometer local temperature probing and remotely controlled drug release based on azo-functionalized iron oxide nanoparticles
      Riedinger, Andreas; Guardia, Pablo; Curcio, Alberto; Garcia, Miguel A.; Cingolani, Roberto; Manna, Liberato; Pellegrino, Teresa
      Nano Letters (2013), 13 (6), 2399-2406CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
      Local heating can be produced by iron oxide nanoparticles (IONPs) when exposed to an alternating magnetic field (AMF). To measure the temp. profile at the nanoparticle surface with a subnanometer resoln., here we present a mol. temp. probe based on the thermal decompn. of a thermo-sensitive mol., namely, azobis[N-(2-carboxyethyl)-2-methylpropionamidine]. Fluoresceineamine (FA) was bound to the azo mol. at the IONP surface functionalized with poly(ethylene glycol) (PEG) spacers of different mol. wts. Significant local heating, with a temp. increase up to 45°, was found at distances below 0.5 nm from the surface of the nanoparticle, which decays exponentially with increasing distance. Furthermore, the temp. increase was found to scale linearly with the applied field at all distances. We implemented these findings in an AMF-triggered drug release system in which doxorubicin was covalently linked at different distances from the IONP surface bearing the same thermo-labile azo mol. We demonstrated the AMF triggered distance-dependent release of the drug in a cytotoxicity assay on KB cancer cells.
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    20. 20
      Thomas, C. R.; Ferris, D. P.; Lee, J.-H.; Choi, E.; Cho, M. H.; Kim, E. S.; Stoddart, J. F.; Shin, J.-S.; Cheon, J.; Zink, J. I. Noninvasive Remote-Controlled Release of Drug Molecules in Vitro Using Magnetic Actuation of Mechanized Nanoparticles. J. Am. Chem. Soc. 2010, 132, 10623– 10625,  DOI: 10.1021/ja1022267
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      Noninvasive Remote-Controlled Release of Drug Molecules in Vitro Using Magnetic Actuation of Mechanized Nanoparticles
      Thomas, Courtney R.; Ferris, Daniel P.; Lee, Jae-Hyun; Choi, Eunjoo; Cho, Mi Hyeon; Kim, Eun Sook; Stoddart, J. Fraser; Shin, Jeon-Soo; Cheon, Jinwoo; Zink, Jeffrey I.
      Journal of the American Chemical Society (2010), 132 (31), 10623-10625CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Mesoporous silica nanoparticles are useful nanomaterials that have demonstrated the ability to contain and release cargos with mediation by gatekeepers. Magnetic nanocrystals have the ability to exhibit hyperthermic effects when placed in an oscillating magnetic field. In a system combining these two materials and a thermally sensitive gatekeeper, a unique drug delivery system can be produced. A novel material that incorporates zinc-doped iron oxide nanocrystals within a mesoporous silica framework that has been surface-modified with pseudorotaxanes is described. Upon application of an AC magnetic field, the nanocrystals generate local internal heating, causing the mol. machines to disassemble and allowing the cargos (drugs) to be released. When breast cancer cells (MDA-MB-231) were treated with doxorubicin-loaded particles and exposed to an AC field, cell death occurred. This material promises to be a noninvasive, externally controlled drug delivery system with cancer-killing properties.
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      Ruiz-Hernandez, E.; Baeza, A.; Vallet-Regi, M. Smart Drug Delivery through DNA/Magnetic Nanoparticle Gates. ACS Nano 2011, 5, 1259– 1266,  DOI: 10.1021/nn1029229
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      Smart Drug Delivery through DNA/Magnetic Nanoparticle Gates
      Ruiz-Hernandez, Eduardo; Baeza, Alejandro; Vallet-Regi, Maria
      ACS Nano (2011), 5 (2), 1259-1266CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Mesoporous silica nanoparticles can be modified to perform on-demand stimuli-responsive dosing of therapeutic mols. The silica network was loaded with iron oxide superparamagnetic nanocrystals, providing the potential to perform targeting and magnetic resonance imaging. Single-stranded DNA was immobilized onto the material surface. The complementary DNA sequence was then attached to magnetic nanoparticles. The present work demonstrates that DNA/magnetic nanoparticle conjugates are able to cap the pores of the magnetic silica particles upon hybridization of both DNA strands. Progressive double-stranded DNA melting as a result of temp. increase gave rise to uncapping and the subsequent release of a mesopore-filled model drug, fluorescein. The reversibility of DNA linkage results in an "on-off" release mechanism. Moreover, the magnetic component of the whole system allows reaching hyperthermic temps. (42-47 °C) under an alternating magnetic field. This feature leaves open the possibility of a remotely triggered drug delivery. Furthermore, due to its capacity to increase the temp. of the surrounding media, this multifunctional device could play an important role in the development of advanced drug delivery systems for thermochemotherapy against cancer.
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      N’Guyen, T. T.; Duong, H. T.; Basuki, J.; Montembault, V.; Pascual, S.; Guibert, C.; Fresnais, J.; Boyer, C.; Whittaker, M. R.; Davis, T. P. Functional Iron Oxide Magnetic Nanoparticles with Hyperthermia-Induced Drug Release Ability by Using a Combination of Orthogonal Click Reactions. Angew. Chem., Int. Ed. Engl. 2013, 125, 14402– 14406,  DOI: 10.1002/anie.201306724
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      Hammad, M.; Nica, V.; Hempelmann, R. On-Command Controlled Drug Release by Diels-Alder Reaction Using Bi-Magnetic Core/Shell Nano-Carriers. Colloids Surf., B 2017, 150, 15– 22,  DOI: 10.1016/j.colsurfb.2016.11.005
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      On-command controlled drug release by Diels-Alder reaction using Bi-magnetic core/shell nano-carriers
      Hammad, Mohaned; Nica, Valentin; Hempelmann, Rolf
      Colloids and Surfaces, B: Biointerfaces (2017), 150 (), 15-22CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)
      A novel bi-functional thermo-responsive system, consisting of core/shell bi-magnetic nanoparticles with furan surface functionality, is bonded with N-(2-Carboxyethyl)maleimide through Diels-Alder reaction. The chemotherapeutics doxorubicin is attached onto the surface, with a high loading efficiency of 92%. This system with high responsiveness to a high frequency external alternating magnetic field shows a very good therapeutic efficiency in hyperthermia and drug release at relatively low temps. (50°C). Polyhedron-shaped bi-magnetic nanoparticles ([email protected]) exhibit a significant increase of the specific energy absorption rate up to 455 W/g compared with the core nanoparticles (200 W/g). Real-time florescence spectroscopy studies demonstrate rapid release of doxorubicin up to 50% in 5 min and up to 92% after 15 min upon exposure to high frequency external alternating magnetic field. The stability is evaluated for 8 wk in phosphate buffer saline with a doxorubicin payload of 85%. In vitro studies using std. MTT cell assays with HeLa and Hep G2 lines prove an excellent biocompatibility with about 90% of cell viability after 24 h of treatment within the highest concn. of functionalized magnetic nanoparticles (200μg/mL). The results indicate a controlled drug release mediated by thermo-responsive switching under applied alternating magnetic field.
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      Guldris, N.; Gallo, J.; García-Hevia, L.; Rivas, J.; Bañobre-López, M.; Salonen, L. M. Orthogonal Clickable Iron Oxide Nanoparticle Platform for Targeting, Imaging, and on-Demand Release. Chem. – A Eur. J. 2018, 24, 8624– 8631,  DOI: 10.1002/chem.201800389
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      Orthogonal Clickable Iron Oxide Nanoparticle Platform for Targeting, Imaging, and On-Demand Release
      Guldris, Noelia; Gallo, Juan; Garcia-Hevia, Lorena; Rivas, Jose; Banobre-Lopez, Manuel; Salonen, Laura M.
      Chemistry - A European Journal (2018), 24 (34), 8624-8631CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A versatile iron oxide nanoparticle platform is reported that can be orthogonally functionalized to obtain highly derivatized nanomaterials required for a wide variety of applications, such as drug delivery, targeted therapy, or imaging. Facile functionalization of the nanoparticles with two ligands contg. isocyanate moieties allows for high coverage of the surface with maleimide and alkyne groups. As a proof-of-principle, the nanoparticles were subsequently functionalized with a fluorophore as a drug model and with biotin as a targeting ligand towards tumor cells through Diels-Alder and azide-alkyne cycloaddn. reactions, resp. The thermoreversibility of the Diels-Alder product was exploited to induce the on-demand release of the loaded mols. by magnetic hyperthermia. Addnl., the nanoparticles were shown to target cancer cells through in vitro expts., as analyzed by magnetic resonance imaging.
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      Wang, L. L.; Balakrishnan, A.; Bigall, N. C.; Candito, D.; Miethe, J. F.; Seidel, K.; Xie, Y.; Ott, M.; Kirschning, A. A Bio-Chemosynthetic Approach to Superparamagnetic Iron Oxide–Ansamitocin Conjugates for Use in Magnetic Drug Targeting. Chem. – Eur. J. 2017, 23, 2265– 2270,  DOI: 10.1002/chem.201604903
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      A Bio-Chemosynthetic Approach to Superparamagnetic Iron Oxide-Ansamitocin Conjugates for Use in Magnetic Drug Targeting
      Wang, Liang-Liang; Balakrishnan, Asha; Bigall, Nadja-Carola; Candito, David; Miethe, Jan Frederick; Seidel, Katja; Xie, Yu; Ott, Michael; Kirschning, Andreas
      Chemistry - A European Journal (2017), 23 (10), 2265-2270CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A combination of mutasynthesis using a mutant strain of A. pretiosum blocked in the biosynthesis of amino-hydroxybenzoic acid (AHBA) and semisynthesis relying on a Stille cross-coupling step provided access to new ansamitocin derivs. of which one was attached by a thermolabile linker to nanostructured iron oxide particles. When exposed to an oscillating electromagnetic field the resulting iron oxide/ansamitocin conjugate 19 heats up in an aq. suspension and the ansamitocin deriv. 16 is released by means of a retro-Diels-Alder reaction. It exerts strong antiproliferative activity (IC50=4.8 ng mg-1) in mouse fibroblasts. These new types of conjugates have the potential for combating cancer through hyperthermia and chemotherapy using an electromagnetic external trigger.
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      Zetterlund, P. B.; Thickett, S. C.; Perrier, S.; Bourgeat-Lami, E.; Lansalot, M. Controlled/Living Radical Polymerization in Dispersed Systems: An Update. Chem. Rev. 2015, 115, 9745– 9800,  DOI: 10.1021/cr500625k
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      Controlled/Living Radical Polymerization in Dispersed Systems: An Update
      Zetterlund, Per B.; Thickett, Stuart C.; Perrier, Sebastien; Bourgeat-Lami, Elodie; Lansalot, Muriel
      Chemical Reviews (Washington, DC, United States) (2015), 115 (18), 9745-9800CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. As alluded to in the Introduction, and as made evident throughout this review, the field of CLRP (controlled/living radical polymn.) in dispersed systems has matured significantly over the past decade. It is now relatively well understood how to best implement CLRP in various (aq.) heterogeneous systems, although challenges still remain. Despite the progress over the past decade,thereare still gaps in fundamental mechanistic understanding, for example, in regard to detailed effects of compartmentalization on CLRP.
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      Matyjaszewski, K.; Spanswick, J. Controlled/Living Radical Polymerization. Mater. Today 2005, 8, 26– 33,  DOI: 10.1016/S1369-7021(05)00745-5
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      Controlled/living radical polymerization
      Matyjaszewski, Krzysztof; Spanswick, James
      Materials Today (Oxford, United Kingdom) (2005), 8 (3), 26-33CODEN: MTOUAN; ISSN:1369-7021. (Elsevier Ltd.)
      A review. Until a little more than a decade ago, controlled/living radical polymn. (CRP) would have been an oxymoron. Full control over all aspects of radical polymn. was deemed well-nigh impossible because radical termination reactions occur at diffusion-controlled rates. However, there are now several procedures for controlling radical polymn., and corporations are introducing products based on CRP into numerous high-value markets. This review briefly summarizes the evolution of CRP, describes some of the materials that can now be prepd., and highlights some of the commercialization efforts currently underway.
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      Boyer, C.; Bulmus, V.; Davis, T. P.; Ladmiral, V.; Liu, J.; Perrier, S. Bioapplications of Raft Polymerization. Chem. Rev. 2009, 109, 5402– 5436,  DOI: 10.1021/cr9001403
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      Bioapplications of RAFT Polymerization
      Boyer, Cyrille; Bulmus, Volga; Davis, Thomas P.; Ladmiral, Vincent; Liu, Jingquan; Perrier, Sebastien
      Chemical Reviews (Washington, DC, United States) (2009), 109 (11), 5402-5436CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review with major subsections entitled Introduction, Functional Polymers Obtained by RAFT, Bioconjugates, Drug Delivery, and Surface Modification by RAFT Polymn. for Biol. Applications.
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      Perrier, S. 50th Anniversary Perspective: Raft Polymerization a User Guide. Macromolecules 2017, 50, 7433– 7447,  DOI: 10.1021/acs.macromol.7b00767
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      50th Anniversary Perspective: RAFT Polymerization-A User Guide
      Perrier, Sebastien
      Macromolecules (Washington, DC, United States) (2017), 50 (19), 7433-7447CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
      A review. This Perspective summarizes the features and limitations of reversible addn.-fragmentation chain transfer (RAFT) polymn., highlighting its strengths and weaknesses, as our understanding of the process, from both a mechanistic and an application point of view, has matured over the past 20 years. It is aimed at both experts in the field and newcomers, including undergraduate and postgraduate students, as well as nonexperts in polymn. who are interested in developing their own polymeric structures by exploiting the simple setup of a RAFT polymn.
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      Pindur, U.; Lutz, G.; Otto, C. Acceleration and Selectivity Enhancement of Diels-Alder Reactions by Special and Catalytic Methods. Chem. Rev. 1993, 93, 741– 761,  DOI: 10.1021/cr00018a006
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      Acceleration and selectivity enhancement of Diels-Alder reactions by special and catalytic methods
      Pindur, Ulf; Lutz, Gundula; Otto, Christian
      Chemical Reviews (Washington, DC, United States) (1993), 93 (2), 741-61CODEN: CHREAY; ISSN:0009-2665.
      Acceleration and selectivity enhancement of Diels-Alder reactions by special and catalytic methods is reviewed with 121 refs.
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      Tasdelen, M. A. Diels–Alder “Click” Reactions: Recent Applications in Polymer and Material Science. Polym. Chem. 2011, 2, 2133– 2145,  DOI: 10.1039/c1py00041a
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      Diels-Alder "click" reactions: recent applications in polymer and material science
      Tasdelen, Mehmet Atilla
      Polymer Chemistry (2011), 2 (10), 2133-2145CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)
      A review. The "click" chem. concept is based on utilizing rapid reactions which are efficient, versatile, and selective. Indeed, Diels-Alder (DA) reactions fulfill most of the requirements for the "click" chem. concept. The authors discuss the recent reports concerned with the use of DA "click" reactions in the synthesis of various macromol. architectures (homopolymers, block and graft copolymers, telechelic polymer), bioconjugates (nucleic acid, peptides), and hybrid materials.
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      Khan, N.; Halder, S.; Gunjan, S.; Prasad, T. A Review on Diels-Alder Based Self-Healing Polymer Composites. IOP Conf. Ser.: Mater. Sci. Eng. 2018, 377, 012007  DOI: 10.1088/1757-899X/377/1/012007
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      A review on Diels-Alder based self-healing polymer composites
      Khan, N. I.; Halder, S.; Gunjan, S. B.; Prasad, T.
      IOP Conference Series: Materials Science and Engineering (2018), 377 (International Conference on Mechanical, Materials and Renewable Energy, 2017), 012007/1-012007/9CODEN: ICSMGW; ISSN:1757-899X. (IOP Publishing Ltd.)
      A review. Self-healing polymers are the materials which can heal the internal cracks or damages automatically without any external intervention. The concept of self-healing has been derived from the biol. systems such as human bone or skin which can heal automatically. This paper reviews the self-healing polymers based on Diels-Alder reaction where diene and dienophile groups form reversible covalent bond between them in the polymer matrix. A comprehensive review on Diels-Alder based self-healing composites reinforced with nanofillers from the last decade have been reported here. The present status followed by future scope in this area has also been discussed briefly at the end of this review.
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      Mai, B. T.; Barthel, M.; Marotta, R.; Pellegrino, T. Crosslinked Ph-Responsive Polymersome Via Diels-Alder Click Chemistry: A Reversible Ph-Dependent Vesicular Nanosystem. Polymer 2019, 165, 19– 27,  DOI: 10.1016/j.polymer.2019.01.022
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      Crosslinked pH-responsive polymersome via Diels-Alder click chemistry: A reversible pH-dependent vesicular nanosystem
      Mai, Binh T.; Barthel, Markus; Marotta, Roberto; Pellegrino, Teresa
      Polymer (2019), 165 (), 19-27CODEN: POLMAG; ISSN:0032-3861. (Elsevier Ltd.)
      Herein, we have developed pH-responsive shape-persistent polymersomes made of well-defined amphiphilic poly(ethylene oxide)-block-poly(diisopropylaminoethyl methacrylate-co-furfuryl methacrylate)s PEO-b-P(DPA-co-FMA) by exploiting Diels-Alder chem. as a robust and simple crosslinking method. Using Photo-induced Copper Mediated Reversible Deactivation Radical Polymn., we synthesized PEO-b-P(DPA-co-FMA) with optimal block ratios that favor the formation of polymersomes in aq. media having pH-responsive P(DPA-co-FMA) membranes. Owing to the existence of furfuryl pendant groups within the polymersome membranes, the crosslinking of pH-responsive P(DPA-co-FMA) chains can be achieved via Diels-Alder chem. Interestingly, the resulting crosslinked polymersomes swell when the pH in the soln. is decreased so that it lies in a biol. relevant range, as was demonstrated by cryogenic transmission electron microscopy. Here, the polymersomes' ability to swell can be controlled by adjusting the amt. of crosslinker. A min. threshold of crosslinking d. is needed for the polymersomes to swell while an excess amt. of crosslinker quenched their ability to swell. Furthermore, crosslinked polymersomes are capable of encapsulating hydrophilic model drug, such as Rhodamine B. At pH 7.20, due to the compact and hydrophobic membrane, the diffusion of the dye from the interior of the polymersomes to the media is minimized, while the pronation of PDPA at an acidic pH of 4.00, enables a permeable membrane, allowing the loaded cargo to leak much more quickly. The shape-persistent polymersomes that we developed herein, are a promising nano-platform for use in drug delivery applications.
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      Goussé, C.; Gandini, A.; Hodge, P. Application of the Diels– Alder Reaction to Polymers Bearing Furan Moieties. 2. Diels– Alder and Retro-Diels– Alder Reactions Involving Furan Rings in Some Styrene Copolymers. Macromolecules 1998, 31, 314– 321,  DOI: 10.1021/ma9710141
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      Application of the Diels-Alder Reaction to Polymers Bearing Furan Moieties. 2. Diels-Alder and Retro-Diels-Alder Reactions Involving Furan Rings in Some Styrene Copolymers
      Gousse, Cecile; Gandini, Alessandro; Hodge, Philip
      Macromolecules (1998), 31 (2), 314-321CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
      Styrene copolymers contg. various amts. of a novel comonomer bearing a pendant furan ring were synthesized and characterized before being submitted to Diels-Alder reactions with either a monomaleimide or a bismaleimide. Spectroscopic evidence, supported by data from model compds., indicated that the resulting linear and crosslinked products contained extensive percentages of adduct structures formed from the furan moieties. Both types of materials were then heated in a solvent contg. a large excess of 2-methylfuran in order to induce the retro-Diels-Alder and the coupling of the released maleimides with the furanic additive. The reaction proceeded as expected and the original copolymers could be recovered from the treatment. The interest in the general strategy reported here resides in the possibility of recycling crosslinked polymers by a simple thermal treatment conducted in the presence of a suitable trap.
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      Dispinar, T.; Sanyal, R.; Sanyal, A. A Diels-Alder/Retro Diels-Alder Strategy to Synthesize Polymers Bearing Maleimide Side Chains. J. Polym. Sci., Part A: Polym. Chem. 2007, 45, 4545– 4551,  DOI: 10.1002/pola.22299
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      A diels-alder/retro diels-alder strategy to synthesize polymers bearing maleimide side chains
      Dispinar, Tugba; Sanyal, Rana; Sanyal, Amitav
      Journal of Polymer Science, Part A: Polymer Chemistry (2007), 45 (20), 4545-4551CODEN: JPACEC; ISSN:0887-624X. (John Wiley & Sons, Inc.)
      Polymers contg. thiol-reactive maleimide groups on their side chains were synthesized by utilization of a novel methacrylate monomer contg. a masked maleimide. Diels-Alder reaction between furan and maleimide was adapted for the protection of the reactive maleimide double bond prior to polymn. AIBN initiated free radical polymn. was utilized for synthesis of copolymers contg. masked maleimide groups. No unmasking of the maleimide group was evident under the polymn. conditions. The maleimide groups in the side chain of the polymers were unmasked into their reactive from by utilization of retro Diels-Alder reaction. This cycloreversion was monitored by thermo gravimetric anal. (TGA), DSC, and 1H and 13C NMR spectroscopy.
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      Discekici, E. H.; St. Amant, A. H.; Nguyen, S. N.; Lee, I.-H.; Hawker, C. J.; Read de Alaniz, J. Endo and Exo Diels–Alder Adducts: Temperature-Tunable Building Blocks for Selective Chemical Functionalization. J. Am. Chem. Soc. 2018, 140, 5009– 5013,  DOI: 10.1021/jacs.8b01544
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      Endo and Exo Diels-Alder Adducts: Temperature-Tunable Building Blocks for Selective Chemical Functionalization
      Discekici, Emre H.; St. Amant, Andre H.; Nguyen, Shay N.; Lee, In-Hwan; Hawker, Craig J.; Read de Alaniz, Javier
      Journal of the American Chemical Society (2018), 140 (15), 5009-5013CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The development and application of a novel endo furan-protected maleimide building block is reported. The endo isomer undergoes deprotection at temps. ∼50 °C below the exo deriv. This enables a simple and powerful approach to quant. and selectively introduce functional maleimide groups via temp. modulation.
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      Oliveira, B.; Guo, Z.; Bernardes, G. Inverse Electron Demand Diels–Alder Reactions in Chemical Biology. Chem. Soc. Rev. 2017, 46, 4895– 4950,  DOI: 10.1039/C7CS00184C
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      Inverse electron demand Diels-Alder reactions in chemical biology
      Oliveira, B. L.; Guo, Z.; Bernardes, G. J. L.
      Chemical Society Reviews (2017), 46 (16), 4895-4950CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      The emerging inverse electron demand Diels-Alder (IEDDA) reaction stands out from other bioorthogonal reactions by virtue of its unmatchable kinetics, excellent orthogonality and biocompatibility. With the recent discovery of novel dienophiles and optimal tetrazine coupling partners, attention has now been turned to the use of IEDDA approaches in basic biol., imaging and therapeutics. Here we review this bioorthogonal reaction and its promising applications for live cell and animal studies. We first discuss the key factors that contribute to the fast IEDDA kinetics and describe the most recent advances in the synthesis of tetrazine and dienophile coupling partners. Both coupling partners have been incorporated into proteins for tracking and imaging by use of fluorogenic tetrazines that become strongly fluorescent upon reaction. Selected notable examples of such applications are presented. The exceptional fast kinetics of this catalyst-free reaction, even using low concns. of coupling partners, make it amenable for in vivo radiolabelling using pretargeting methodologies, which are also discussed. Finally, IEDDA reactions have recently found use in bioorthogonal decaging to activate proteins or drugs in gain-of-function strategies. We conclude by showing applications of the IEDDA reaction in the construction of biomaterials that are used for drug delivery and multimodal imaging, among others. The use and utility of the IEDDA reaction is interdisciplinary and promises to revolutionize chem. biol., radiochem. and materials science.
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    38. 38
      Guardia, P.; Di Corato, R.; Lartigue, L.; Wilhelm, C.; Espinosa, A.; Garcia-Hernandez, M.; Gazeau, F.; Manna, L.; Pellegrino, T. Water-Soluble Iron Oxide Nanocubes with High Values of Specific Absorption Rate for Cancer Cell Hyperthermia Treatment. ACS Nano 2012, 6, 3080– 3091,  DOI: 10.1021/nn2048137
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      Water-Soluble Iron Oxide Nanocubes with High Values of Specific Absorption Rate for Cancer Cell Hyperthermia Treatment
      Guardia, Pablo; Di Corato, Riccardo; Lartigue, Lenaic; Wilhelm, Claire; Espinosa, Ana; Garcia-Hernandez, Mar; Gazeau, Florence; Manna, Liberato; Pellegrino, Teresa
      ACS Nano (2012), 6 (4), 3080-3091CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Iron oxide nanocrystals (IONCs) are appealing heat mediator nanoprobes in magnetic-mediated hyperthermia for cancer treatment. Here, specific absorption rate (SAR) values are reported for cube-shaped water-sol. IONCs prepd. by a one-pot synthesis approach in a size range between 13 and 40 nm. The SAR values were detd. as a function of frequency and magnetic field applied, also spanning tech. conditions which are considered biomedically safe for patients. Among the different sizes tested, IONCs with an av. diam. of 19 ± 3 nm had significant SAR values in clin. conditions and reached SAR values up to 2452 W/gFe at 520 kHz and 29 kAm-1, which is one of the highest values so far reported for IONCs. In vitro trials carried out on KB cancer cells treated with IONCs of 19 nm have shown efficient hyperthermia performance, with cell mortality of about 50% recorded when an equil. temp. of 43 °C was reached after 1 h of treatment.
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      Kolosnjaj-Tabi, J.; Di Corato, R.; Lartigue, L.; Marangon, I.; Guardia, P.; Silva, A. K.; Luciani, N.; Clement, O.; Flaud, P.; Singh, J. V. Heat-Generating Iron Oxide Nanocubes: Subtle “Destructurators” of the Tumoral Microenvironment. ACS Nano 2014, 8, 4268– 4283,  DOI: 10.1021/nn405356r
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      Heat-Generating Iron Oxide Nanocubes: Subtle "Destructurators" of the Tumoral Microenvironment
      Kolosnjaj-Tabi, Jelena; Di Corato, Riccardo; Lartigue, Lenaic; Marangon, Iris; Guardia, Pablo; Silva, Amanda K. A.; Luciani, Nathalie; Clement, Olivier; Flaud, Patrice; Singh, Jaykrishna V.; Decuzzi, Paolo; Pellegrino, Teresa; Wilhelm, Claire; Gazeau, Florence
      ACS Nano (2014), 8 (5), 4268-4283CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Several studies propose nanoparticles for tumor treatment, yet little is known about the fate of nanoparticles and intimate interactions with the heterogeneous and ever-evolving tumor environment. The latter, rich in extracellular matrix, is responsible for poor penetration of therapeutics and represents a paramount issue in cancer therapy. Hence new strategies start aiming to modulate the neoplastic stroma. From this perspective, we assessed the efficacy of 19 nm PEG-coated iron oxide nanocubes with optimized magnetic properties to mediate mild tumor magnetic hyperthermia treatment. After injection of a low dose of nanocubes (700 μg of iron) into epidermoid carcinoma xenografts in mice, we monitored the effect of heating nanocubes on tumor environment. In comparison with the long-term fate after i.v. administration, we investigated spatiotemporal patterns of nanocube distribution, evaluated the evolution of cubes magnetic properties, and examd. nanoparticle clearance and degrdn. processes. While inside tumors nanocubes retained their magnetic properties and heating capacity throughout the treatment due to a mainly interstitial extracellular location, the particles became inefficient heaters after cell internalization and transfer to spleen and liver. Our multiscale anal. reveals that collagen-rich tumor extracellular matrix confines the majority of nanocubes. However, nanocube-mediated hyperthermia has the potential to "destructure" this matrix and improve nanoparticle and drug penetration into neoplastic tissue. This study provides insight into dynamic interactions between nanoparticles and tumor components under phys. stimulation and suggests that nanoparticle-mediated hyperthermia could be used to locally modify tumor stroma and thus improve drug penetration.
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    40. 40
      Espinosa, A.; Di Corato, R.; Kolosnjaj-Tabi, J.; Flaud, P.; Pellegrino, T.; Wilhelm, C. Duality of Iron Oxide Nanoparticles in Cancer Therapy: Amplification of Heating Efficiency by Magnetic Hyperthermia and Photothermal Bimodal Treatment. ACS Nano 2016, 10, 2436– 2446,  DOI: 10.1021/acsnano.5b07249
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      Duality of Iron Oxide Nanoparticles in Cancer Therapy: Amplification of Heating Efficiency by Magnetic Hyperthermia and Photothermal Bimodal Treatment
      Espinosa, Ana; Di Corato, Riccardo; Kolosnjaj-Tabi, Jelena; Flaud, Patrice; Pellegrino, Teresa; Wilhelm, Claire
      ACS Nano (2016), 10 (2), 2436-2446CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      The pursuit of innovative, multifunctional, more efficient, and safer treatments is a major challenge in preclin. nanoparticle-mediated thermotherapeutic research. Here, we report that iron oxide nanoparticles have the dual capacity to act as both magnetic and photothermal agents. We further explore every key aspect of this magnetophotothermal approach, choosing iron oxide nanocubes for their high efficiency for the magnetic hyperthermia modality itself. In aq. suspension, the nanocubes' exposure to both: an alternating magnetic field and near-IR laser irradn. (808 nm), defined as the DUAL-mode, amplifies the heating effect 2- to 5-fold by comparison with magnetic stimulation alone, yielding unprecedented heating powers (specific loss powers) up to 5000 W/g. In cancer cells, the laser excitation restores the optimal efficiency of magnetic hyperthermia, otherwise inhibited by intracellular confinement, resulting in a remarkable heating efficiency in the DUAL-mode (up to 15-fold amplification), with respect to the magnetophotothermal mode. As a consequence, the dual action yielded complete apoptosis-mediated cell death. In solid tumors in vivo, single-mode treatments (magnetic or laser hyperthermia) reduced tumor growth, while DUAL-mode treatment resulted in complete tumor regression, mediated by heat-induced tumoral cell apoptosis and massive denaturation of the collagen fibers, and a long-lasting thermal efficiency over repeated treatments.
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      Materia, M. E.; Guardia, P.; Sathya, A.; Pernia Leal, M.; Marotta, R.; Di Corato, R.; Pellegrino, T. Mesoscale Assemblies of Iron Oxide Nanocubes as Heat Mediators and Image Contrast Agents. Langmuir 2015, 31, 808– 816,  DOI: 10.1021/la503930s
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      Mesoscale Assemblies of Iron Oxide Nanocubes as Heat Mediators and Image Contrast Agents
      Materia, Maria Elena; Guardia, Pablo; Sathya, Ayyappan; Pernia Leal, Manuel; Marotta, Roberto; Di Corato, Riccardo; Pellegrino, Teresa
      Langmuir (2015), 31 (2), 808-816CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
      Iron oxide nanocubes (IONCs) represent one of the most promising iron-based nanoparticles for both magnetic resonance image (MRI) and magnetically mediated hyperthermia (MMH). Here, we have set a protocol to control the aggregation of magnetically interacting IONCs within a polymeric matrix in a so-called magnetic nanobead (MNB) having mesoscale size (200 nm). By the comparison with individual coated nanocubes, we elucidate the effect of the aggregation on the specific adsorption rates (SAR) and on the T1 and T2 relaxation times. We found that while SAR values decrease as IONCs are aggregated into MNBs but still keeping significant SAR values (200 W/g at 300 kHz), relaxation times show very interesting properties with outstanding values of r2/r1 ratio for the MNBs with respect to single IONCs.
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      Champagne, P.-O.; Westwick, H.; Bouthillier, A.; Sawan, M. Colloidal Stability of Superparamagnetic Iron Oxide Nanoparticles in the Central Nervous System: A Review. Nanomedicine 2018, 13, 1385– 1400,  DOI: 10.2217/nnm-2018-0021
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      Colloidal stability of superparamagnetic iron oxide nanoparticles in the central nervous system: a review
      Champagne, Pierre-Olivier; Westwick, Harrison; Bouthillier, Alain; Sawan, Mohamad
      Nanomedicine (London, United Kingdom) (2018), 13 (11), 1385-1400CODEN: NLUKAC; ISSN:1748-6963. (Future Medicine Ltd.)
      Superparamagnetic iron oxide nanoparticles (SPIONs) consist of nanosized metallic-based particles with unique magnetic properties. Their potential in both diagnostic and therapeutic applications in the CNS is at the source of an expanding body of the literature in recent years. Colloidal stability of nanoparticles represents their ability to resist aggregation and is a central aspect for the use of SPION in biol. environment such as the CNS. This review gives a comprehensive update of the recent developments and knowledge on the determinants of colloidal stability of SPIONs in the CNS. Factors leading to aggregate formation and the repercussions of colloidal instability of SPION are reviewed in detail pertaining to their use in the CNS.
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      Palui, G.; Aldeek, F.; Wang, W.; Mattoussi, H. Strategies for Interfacing Inorganic Nanocrystals with Biological Systems Based on Polymer-Coating. Chem. Soc. Rev. 2015, 44, 193– 227,  DOI: 10.1039/C4CS00124A
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      Strategies for interfacing inorganic nanocrystals with biological systems based on polymer-coating
      Palui, Goutam; Aldeek, Fadi; Wang, Wentao; Mattoussi, Hedi
      Chemical Society Reviews (2015), 44 (1), 193-227CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. Interfacing inorg. nanoparticles and biol. systems with the aim of developing novel imaging and sensing platforms has generated great interest and much activity. However, the effectiveness of this approach hinges on the ability of the surface ligands to promote water-dispersion of the nanoparticles with long term colloidal stability in buffer media. These surface ligands protect the nanostructures from the harsh biol. environment, while allowing coupling to target mols., which can be biol. in nature (e.g., proteins and peptides) or exhibit specific photo-phys. characteristics (e.g., a dye or a redox-active mol.). Amphiphilic block polymers have provided researchers with versatile mol. platforms with tunable size, compn. and chem. properties. Hence, several groups have developed a wide range of polymers as ligands or micelle capsules to promote the transfer of a variety of inorg. nanomaterials to buffer media (including magnetic nanoparticles and semiconductor nanocrystals) and render them biocompatible. In this review, we first summarize the established synthetic routes to grow high quality nanocrystals of semiconductors, metals and metal oxides. We then provide a crit. evaluation of the recent developments in the design, optimization and use of various amphiphilic copolymers to surface functionalize the above nanocrystals, along with the strategies used to conjugate them to target biomols. We finally conclude by providing a summary of the most promising applications of these polymer-coated inorg. platforms in sensor design, and imaging of cells and tissues.
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      Ling, D.; Lee, N.; Hyeon, T. Chemical Synthesis and Assembly of Uniformly Sized Iron Oxide Nanoparticles for Medical Applications. Acc. Chem. Res. 2015, 48, 1276– 1285,  DOI: 10.1021/acs.accounts.5b00038
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      Chemical Synthesis and Assembly of Uniformly Sized Iron Oxide Nanoparticles for Medical Applications
      Ling, Daishun; Lee, Nohyun; Hyeon, Taeghwan
      Accounts of Chemical Research (2015), 48 (5), 1276-1285CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
      A review. Magnetic iron oxide nanoparticles have been extensively investigated for their various biomedical applications including diagnostic imaging, biol. sensing, drug, cell, and gene delivery, and cell tracking. Recent advances in the designed synthesis and assembly of uniformly sized iron oxide nanoparticles have brought innovation in the field of nanomedicine. This Account provides a review on the recent progresses in the controlled synthesis and assembly of uniformly sized iron oxide nanoparticles for medical applications. In particular, it focuses on three topics: stringent control of particle size during synthesis via the "heat-up" process, surface modification for the high stability and biocompatibility of the nanoparticles for diagnostic purposes, and assembly of the nanoparticles within polymers or mesoporous silica matrixes for theranostic applications. Using extremely small 3 nm sized iron oxide nanoparticles (ESION), a new nontoxic T1 MRI contrast agent was realized for high-resoln. MRI of blood vessels down to 0.2 mm. Ferrimagnetic iron oxide nanoparticles (FION) that are larger than 20 nm exhibit extremely large magnetization and coercivity values. The cells labeled with FIONs showed very high T2 contrast effect so that even a single cell can be readily imaged. Designed assembly of iron oxide nanoparticles with mesoporous silica and polymers was conducted to fabricate multifunctional nanoparticles for theranostic applications. Mesoporous silica nanoparticles are excellent scaffolds for iron oxide nanoparticles, providing magnetic resonance and fluorescence imaging modalities as well as the functionality of the drug delivery vehicle. Polymeric ligands could be designed to respond to various biol. stimuli such as pH, temp., and enzymic activity. For example, we fabricated tumor pH-sensitive magnetic nanogrenades (termed PMNs) composed of self-assembled iron oxide nanoparticles and pH-responsive ligands. They were utilized to visualize small tumors (<3 mm) via pH-responsive T1 MRI and fluorescence imaging. Also, superior photodynamic therapeutic efficacy in highly drug-resistant heterogeneous tumors was obsd. We expect that these multifunctional and bioresponsive nanoplatforms based on uniformly sized iron oxide nanoparticles will provide more unique theranostic approaches in clin. uses.
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      Wu, W.; Jiang, C. Z.; Roy, V. A. Designed Synthesis and Surface Engineering Strategies of Magnetic Iron Oxide Nanoparticles for Biomedical Applications. Nanoscale 2016, 8, 19421– 19474,  DOI: 10.1039/C6NR07542H
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      Designed synthesis and surface engineering strategies of magnetic iron oxide nanoparticles for biomedical applications
      Wu, Wei; Jiang, Chang Zhong; Roy, Vellaisamy A. L.
      Nanoscale (2016), 8 (47), 19421-19474CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
      A review. Iron oxide nanoparticles (NPs) hold great promise for future biomedical applications because of their magnetic properties as well as other intrinsic properties such as low toxicity, colloidal stability, and surface engineering capability. Numerous related studies on iron oxide NPs have been conducted. Recent progress in nanochem. has enabled fine control over the size, crystallinity, uniformity, and surface properties of iron oxide NPs. This review examines various synthetic approaches and surface engineering strategies for prepg. naked and functional iron oxide NPs with different physicochem. properties. Growing interest in designed and surface-engineered iron oxide NPs with multifunctionalities was explored in in vitro/in vivo biomedical applications, focusing on their combined roles in biosepn., as a biosensor, targeted-drug delivery, MR contrast agents, and magnetic fluid hyperthermia. This review outlines the limitations of extant surface engineering strategies and several developing strategies that may overcome these limitations. This study also details the promising future directions of this active research field.
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      Schubert, J.; Chanana, M. Coating Matters: Review on Colloidal Stability of Nanoparticles with Biocompatible Coatings in Biological Media, Living Cells and Organisms. Curr. Med. Chem. 2019, 25, 4556,  DOI: 10.2174/0929867325666180601101859
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      Garbin, V.; Crocker, J. C.; Stebe, K. J. Nanoparticles at Fluid Interfaces: Exploiting Capping Ligands to Control Adsorption, Stability and Dynamics. J. Colloid Interface Sci. 2012, 387, 1– 11,  DOI: 10.1016/j.jcis.2012.07.047
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      Nanoparticles at fluid interfaces: Exploiting capping ligands to control adsorption, stability and dynamics
      Garbin, Valeria; Crocker, John C.; Stebe, Kathleen J.
      Journal of Colloid and Interface Science (2012), 387 (1), 1-11CODEN: JCISA5; ISSN:0021-9797. (Elsevier B.V.)
      A review. Nanoparticle self-assembly at fluid-fluid interfaces has been traditionally exploited in emulsification, encapsulation, and oil recovery, and more recently in emerging applications including functional nanomaterials and biphasic catalysis. A review of the literature focusing on the open challenges that still hamper the broader applicability of this potentially transformative technol. is provided, and strategies to achieve improved control over interfacial self-assembly of nanoparticles are outlined. Means to promote spontaneous adsorption by tuning the interfacial energies of the nanoparticles with the fluids using capping ligands and the occurrence of energy barriers are discussed. The interactions between interfacial nanoparticles and how they affect the formation of equil. interfacial suspensions vs. non-equil. two-dimensional phases, such as weakly attractive glasses and gels, are discussed. Important differences with colloidal interactions in a bulk suspension arise due to the discontinuity in solvent properties at the interface. For instance, ligand brushes rearrange in asym. configurations, and thus play a significant role in detg. interparticle interactions. Finally, the link between interfacial microstructure and the dynamic response of particle-laden interfaces, including interfacial rheol. and the fate of nanoparticle monolayers upon out-of-plane deformation, are discussed.
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      Na, H. B.; Palui, G.; Rosenberg, J. T.; Ji, X.; Grant, S. C.; Mattoussi, H. Multidentate Catechol-Based Polyethylene Glycol Oligomers Provide Enhanced Stability and Biocompatibility to Iron Oxide Nanoparticles. ACS Nano 2012, 6, 389– 399,  DOI: 10.1021/nn203735b
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      Multidentate Catechol-Based Polyethylene Glycol Oligomers Provide Enhanced Stability and Biocompatibility to Iron Oxide Nanoparticles
      Na, Hyon Bin; Palui, Goutam; Rosenberg, Jens T.; Ji, Xin; Grant, Samuel C.; Mattoussi, Hedi
      ACS Nano (2012), 6 (1), 389-399CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      We have designed, prepd., and tested a new set of multidentate catechol- and polyethylene glycol (PEG)-derivatized oligomers, OligoPEG-Dopa, as ligands that exhibit strong affinity to iron oxide nanocrystals. The ligands consist of a short poly(acrylic acid) backbone laterally appended with several catechol anchoring groups and several terminally functionalized PEG moieties to promote affinity to aq. media and to allow further coupling to target mols. (bio and others). These multicoordinating PEGylated oligomers were prepd. using a relatively simple chem. strategy based on N,N'-dicyclohexylcarbodiimide (DCC) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) condensation. The ability of these catechol-functionalized oligomers to impart long-term colloidal stability to the nanoparticles is compared to other control ligands, namely, oligomers presenting several carboxyl groups and monodentate ligands presenting either one catechol or one carboxyl group. We found that the OligoPEG-Dopa ligands provide rapid ligand exchange, and the resulting nanoparticles exhibit greatly enhanced colloidal stability over a broad pH range and in the presence of excess electrolytes; stability is notably improved compared to non-catechol presenting mol. or oligomer ligands. By inserting controllable fractions of azide-terminated PEG moieties, the nanoparticles (NPs) become reactive to complementary functionalities via azide-alkyne cycloaddn. (Click), which opens up the possibility of biol. targeting of such stable NPs. In particular, we tested the Click coupling of azide-functionalized nanoparticles to an alkyne-modified dye. We also measured the MRI T2 contrast of the OligoPEG-capped Fe3O4 nanoparticles and applied MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay to test the potential cytotoxicity of these NPs to live cells; we found no measurable toxicity to live cells.
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      Amstad, E.; Gillich, T.; Bilecka, I.; Textor, M.; Reimhult, E. Ultrastable Iron Oxide Nanoparticle Colloidal Suspensions Using Dispersants with Catechol-Derived Anchor Groups. Nano Lett. 2009, 9, 4042– 4048,  DOI: 10.1021/nl902212q
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      Ultrastable Iron Oxide Nanoparticle Colloidal Suspensions using Dispersants with Catechol-Derived Anchor Groups
      Amstad, Esther; Gillich, Torben; Bilecka, Idalia; Textor, Marcus; Reimhult, Erik
      Nano Letters (2009), 9 (12), 4042-4048CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
      The authors found catechol-deriv. anchor groups which possess irreversible binding affinity to iron oxide and thus can optimally disperse superparamagnetic nanoparticles under physiol. conditions. This not only leads to ultrastable iron oxide nanoparticles but also allows close control over the hydrodynamic diam. and interfacial chem. The latter is a crucial breakthrough to assemble functionalized magnetic nanoparticles, e.g., as targeted magnetic resonance contrast agents.
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      Xiao, W.; Legros, P.; Chevallier, P.; Lagueux, J.; Oh, J. K.; Fortin, M.-A. Superparamagnetic Iron Oxide Nanoparticles Stabilized with Multidentate Block Copolymers for Optimal Vascular Contrast in T 1-Weighted Magnetic Resonance Imaging. ACS Appl. Nano Mater. 2018, 1, 894– 907,  DOI: 10.1021/acsanm.7b00300
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      Superparamagnetic Iron Oxide Nanoparticles Stabilized with Multidentate Block Copolymers for Optimal Vascular Contrast in T1-Weighted Magnetic Resonance Imaging
      Xiao, Wangchuan; Legros, Philippe; Chevallier, Pascale; Lagueux, Jean; Oh, Jung Kwon; Fortin, Marc-Andre
      ACS Applied Nano Materials (2018), 1 (2), 894-907CODEN: AANMF6; ISSN:2574-0970. (American Chemical Society)
      Ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) have been used as vascular contrast agents in magnetic resonance imaging (MRI), mainly for their capacity to generate neg. contrast. To use USPIOs as pos. contrast agents, it is necessary to achieve increased colloidal stability and signal-enhancement performance. Their mol. coatings must be carefully chosen, so that the vascular blood-pool contrast agents lead to long blood turnover times. However, to avoid long-term toxicol. effects, they must also be cleared rapidly through the urinary or gastrointestinal pathways. In this context, highly stable USPIOs showing "pos." contrast in MRI and optimal clearance rates call for the development of robust biocompatible mol. coatings. USPIOs were stabilized with a multidentate block copolymer (MDBC), using a one-pot polyol synthesis method in the presence of a MDBC. Two types of MDBCs having pendant COOH groups in the anchoring block were developed: a polymer with linear-poly(ethylene glycol) (PEG) blocks and a polymer contg. brushed-PEG blocks. The synthesized superparamagnetic Fe3O4 crystals were uniform (5-8 nm in diam.), showed ultrasmall hydrodynamic diams. in dynamic light scattering, and were stable in physiol. liqs. MDBC-coated USPIOs were analyzed in relaxometry, and the formulations showing the strongest potential for T1-weighted vascular imaging (r2/r1: ∼4) were selected for in vivo MRI. Intravascular injections performed in the mouse model indicated long blood retention times and high signal enhancement in MRI for nanoparticles coated with linear-PEG block coatings. Also MDBC/USPIOs could be used in vascular MRI applications, where the nanoparticles must transit the blood for several hours, followed by an efficient clearance in the next days following injection. The use of MDBCs as nanoparticle coatings could open new possibilities in the design of USPIOs for targeted mol. MRI.
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      Wang, W.; Ji, X.; Na, H. B.; Safi, M.; Smith, A.; Palui, G.; Perez, J. M.; Mattoussi, H. Design of a Multi-Dopamine-Modified Polymer Ligand Optimally Suited for Interfacing Magnetic Nanoparticles with Biological Systems. Langmuir 2014, 30, 6197– 6208,  DOI: 10.1021/la500974r
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      Design of a Multi-Dopamine-Modified Polymer Ligand Optimally Suited for Interfacing Magnetic Nanoparticles with Biological Systems
      Wang, Wentao; Ji, Xin; Na, Hyon Bin; Safi, Malak; Smith, Alexandra; Palui, Goutam; Perez, J. Manuel; Mattoussi, Hedi
      Langmuir (2014), 30 (21), 6197-6208CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
      We have designed a set of multifunctional and multicoordinating polymer ligands that are optimally suited for surface functionalizing iron oxide and potentially other magnetic nanoparticles (NPs) and promoting their integration into biol. systems. The amphiphilic polymers are prepd. by coupling (via nucleophilic addn.) several amine-terminated dopamine anchoring groups, poly(ethylene glycol) moieties, and reactive groups onto a poly(isobutylene-alt-maleic anhydride) (PIMA) chain. This design greatly benefits from the highly efficient and reagent-free one-step reaction of maleic anhydride groups with amine-contg. mols. The availability of several dopamine groups in the same ligand greatly enhances the ligand affinity, via multiple coordination, to the magnetic NPs, while the hydrophilic and reactive groups promote colloidal stability in buffer media and allow subsequent conjugation with target biomols. Iron oxide nanoparticles ligand exchanged with these polymer ligands have a compact hydrodynamic size and exhibit enhanced long-term colloidal stability over the pH range of 4-12 and in the presence of excess electrolytes. Nanoparticles ligated with terminally reactive polymers have been easily coupled to target dyes and tested in live cell imaging with no measurable cytotoxicity. Finally, the resulting hydrophilic nanoparticles exhibit large and size-dependent r2 relaxivity values.
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      Wang, W.; Mattoussi, H. Engineering the Bio–Nano Interface Using a Multifunctional Coordinating Polymer Coating. Acc. Chem. Res. 2020, 53, 1124– 1138,  DOI: 10.1021/acs.accounts.9b00641
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      Engineering the Bio-Nano Interface Using a Multifunctional Coordinating Polymer Coating
      Wang, Wentao; Mattoussi, Hedi
      Accounts of Chemical Research (2020), 53 (6), 1124-1138CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
      A review. Conspectus: In the past three decades, interest in using nanoparticles as diagnostic tools to interrogate various biosystems has witnessed remarkable growth. For instance, it has been shown that nanoparticle probes enable the study of cellular processes at the single mol. level. These advances provide new opportunities for understanding fundamental problems in biol., innovation in medicine, and the treatment of diseases. A multitude of nanoparticles have been designed to facilitate in vitro or in vivo sensing, imaging, and diagnostics. Some of those nanoparticle platforms are currently in clin. trials or have been approved by the U.S. Food and Drug Administration. Nonetheless, using nanoparticles in biol. is still facing several obstacles, such as poor colloidal stability under physiol. conditions, nonspecific interactions with serum proteins, and low targeting efficiency in biol. fluids, in addn. to issues of uncontrolled biodistribution and cytotoxicity. All these problems are primarily controlled by the surface stabilizing coating used. In this Account, we summarize recent progress made in our lab. focused on the development of multifunctional polymers as coordinating ligands, to tailor the surface properties of nanoparticles and facilitate their application in biol. We first detail the advantageous features of the coating strategy, followed by a discussion of the key parameters in the ligand design. We then describe the synthesis and use of a series of multicoordinating polymers as ligands optimized for coating quantum dots (QDs), gold nanoparticles (AuNPs), and magnetic nanoparticles (MNPs), with a focus on (i) how to improve the colloidal stability and antifouling performance of materials in biol. conditions; (ii) how to design highly compact coating, without compromising colloidal stability; and (iii) how to tailor the surface functionalities to achieve conjugation to target biomols. We also highlight the ability of a phase transfer strategy, mediated by UV irradn., to promote rapid ligand exchange while preserving the integrity of key functional groups. We then summarize the bioconjugation approaches applied to polymer-coated nanoparticles, with emphasis on the ability of metal-histidine self-assembly and click chem., to control the final nanoparticle bioconjugates. Finally, we demonstrate the use of polymer-coated nanoparticles for sensor design based on redox-active interactions and peptide-mediated intracellular delivery. We anticipate that the coating design presented in this Account would advance the integration of nanoparticles into biol. and medicine.
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    53. 53
      Mai, B. T.; Barthel, M. J.; Lak, A.; Avellini, T.; Panaite, A. M.; Rodrigues, E. M.; Goldoni, L.; Pellegrino, T. Photo-Induced Copper Mediated Copolymerization of Activated-Ester Methacrylate Polymers and Their Use as Reactive Precursors to Prepare Multi-Dentate Ligands for the Water Transfer of Inorganic Nanoparticles. Polym. Chem. 2020, 11, 2969– 2985,  DOI: 10.1039/D0PY00212G
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      53
      Photo-induced copper mediated copolymerization of activated-ester methacrylate polymers and their use as reactive precursors to prepare multi-dentate ligands for the water transfer of inorganic nanoparticles
      Mai, Binh T.; Barthel, Markus J.; Lak, Aidin; Avellini, Tommaso; Panaite, Ana Maria; Rodrigues, Emille M.; Goldoni, Luca; Pellegrino, Teresa
      Polymer Chemistry (2020), 11 (17), 2969-2985CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)
      Multi-dentate ligands enabling a quick and high yield water transfer of inorg. nanocrystals (NCs) via a ligand exchange process is of great interest to promote the applications of NCs in the biomedical field. Here, we describe a facile two-step protocol for the synthesis of polymeric multi-dentate ligands that are suitable for the water transfer of hydrophobic colloidal inorg. nanocrystals (NCs). This protocol first exploits the photo-induced atom transfer radical (photo-ATRP) copolymn. of ester-activated N-succinimidyl methacrylate and oligoethylene glycol Me ether methacrylate. A high monomer conversion rate along with a fair control over the polymn. is confirmed by size exclusion chromatog. and NMR spectroscopy. In the second step, the activated carboxyl moieties of the copolymers are reacted with nucleophilic agents such as 2-aminoethylphosphonic acid or histamine dihydrochloride via a post-polymn. reaction to generate phosphonic- or amino-based multi-dentate ligands, resp. As shown here, polymers comprising poly-phosphonic acid moieties are suitable as multi-dentate ligands for water transfer of multiple varieties of NCs with distinct compns. including iron oxide nanoparticles, CdSe@CdS quantum dots (QDs) and up-converting nanoparticles (UCNPs). Meanwhile the polymers contg. histamine groups are also able to strongly coordinate to the surface of semiconductor QDs, thus enabling their water transfer. Notably, the NCs exhibit long-term stability in physiol. media (saline) upon water transfer, while their size, shape, magnetic properties, and optical properties were also maintained. The UCNPs could be imaged when excited under an IR laser while the QDs show a bright fluorescence signal under UV irradn. QDs coated with a poly-phosphonic acid-based ligand resulted in a more homogeneous coating as demonstrated by the narrow band on gel electrophoresis, along with a higher quantum yield (QY ~ 48%) in comparison with the polyimidazole-based ones (QY ~ 31%). The aq. IONPs instead were proven to provide a transversal relaxation making them useful as contrast agents in magnetic resonance imaging. The water transfer procedure is straightforward thanks to the full soly. of the amphiphilic polymer in the NC chloroform soln. This enables the right interaction between the anchoring moieties on the polymer chains and the surface of NCs, thus replacing the surfactant mols. The gram scale prodn. of the polymer together with the very simple steps of the water transfer protocol enables a quick translation of the protocol for large scale prodn. of aq. stabilized nanoparticles.
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    54. 54
      Pellegrino, T.; Rubio, H. G.; Mai, B. T.; Cingolani, R. Method for the Gram-Scale Preparation of Cubic Ferrite Nanocrystals for Biomedical Applications . Google Patents 2022.
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      Cabrera, D.; Lak, A.; Yoshida, T.; Materia, M.; Ortega, D.; Ludwig, F.; Guardia, P.; Sathya, A.; Pellegrino, T.; Teran, F. Unraveling Viscosity Effects on the Hysteresis Losses of Magnetic Nanocubes. Nanoscale 2017, 9, 5094– 5101,  DOI: 10.1039/C7NR00810D
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      55
      Unraveling viscosity effects on the hysteresis losses of magnetic nanocubes
      Cabrera, D.; Lak, A.; Yoshida, T.; Materia, M. E.; Ortega, D.; Ludwig, F.; Guardia, P.; Sathya, A.; Pellegrino, T.; Teran, F. J.
      Nanoscale (2017), 9 (16), 5094-5101CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
      Hysteresis losses in magnetic nanoparticles constitute the basis of magnetic hyperthermia for delivering a local thermal stress. Nevertheless, this therapeutic modality is only to be realized through a careful appraisal of the best possible intrinsic and extrinsic conditions to the nanoparticles for which they maximize and preserve their heating capabilities. Low frequency (100 kHz) hysteresis loops accurately probe the dynamical magnetic response of magnetic nanoparticles in a more reliable manner than calorimetry measurements, providing conclusive quant. data under different exptl. conditions. We consider here a set of iron oxide or cobalt ferrite nanocubes of different sizes, through which we exptl. and theor. study the influence of the viscosity of the medium on the low frequency hysteresis loops of magnetic colloids, and hence their ability to produce and dissipate heat to the surroundings. We analyze the role of nanoparticle size, size distribution, chem. compn., and field intensity in making the magnetization dynamics sensitive to viscosity. Numerical simulations using the stochastic Landau-Lifshitz-Gilbert equation model the exptl. observations in excellent agreement. These results represent an important contribution towards predicting viscosity effects and hence to maximize heat dissipation from magnetic nanoparticles regardless of the environment.
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    56. 56
      Das, R.; Alonso, J.; Nemati Porshokouh, Z.; Kalappattil, V.; Torres, D.; Phan, M.-H.; Garaio, E.; García, J. A. N.; Sanchez Llamazares, J. L.; Srikanth, H. Tunable High Aspect Ratio Iron Oxide Nanorods for Enhanced Hyperthermia. J. Phys. Chem. C 2016, 120, 10086– 10093,  DOI: 10.1021/acs.jpcc.6b02006
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      Tunable High Aspect Ratio Iron Oxide Nanorods for Enhanced Hyperthermia
      Das, Raja; Alonso, Javier; Nemati Porshokouh, Zohreh; Kalappattil, Vijaysankar; Torres, David; Phan, Manh-Huong; Garaio, Eneko; Garcia, Jose Angel; Sanchez Llamazares, Jose Luis; Srikanth, Hariharan
      Journal of Physical Chemistry C (2016), 120 (18), 10086-10093CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
      Despite magnetic hyperthermia being considered one of the most promising techniques for cancer treatment, until now spherical magnetite (Fe3O4) or maghemite (γ-Fe2O3) nanoparticles, which are the most commonly employed and only FDA approved materials, yield the limited heating capacity. Therefore, there is an increasing need for new strategies to improve the heating efficiency or the specific absorption rate (SAR) of these nanosystems. Recently, a large improvement in SAR has been reported for nanocubes of Fe3O4 relative to their spherical counterpart, as a result of their enhanced surface anisotropy and chainlike particle formation. Considering the proven advantages of high aspect ratio one-dimensional (1D) Fe3O4 nanostructures over their spherical and cubic counterparts, such as larger surface area, multisegmented capabilities, enhanced blood circulation time, and prolonged retention in tumors, we propose a novel approach that utilizes this 1D nanostructure for enhanced hyperthermia. Here, we demonstrate that the SAR of iron oxide nanostructures can be enhanced and tuned by altering their aspect ratio. Calorimetric and ac magnetometry expts. performed for the first time on highly cryst. Fe3O4 nanorods consistently show large SAR values (862 W/g for an ac field of 800 Oe), which are superior to spherical and cubic nanoparticles of similar vol. (∼140 and ∼314 W/g, resp.). Increasing the aspect ratio of the nanorods from 6 to 11 improves the SAR by 1.5 times. The nanorods are rapidly aligned by the applied ac field, which appreciably increases the SAR values. A detailed anal. of the effect of the alignment of the nanorods in agar indicates an appreciable SAR increase up to 30% when the nanorods are parallel to the field. These findings pave a new pathway for the design of novel high-aspect ratio magnetic nanostructures for advanced hyperthermia.
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    57. 57
      Cai, T.; Chen, L.; Ren, Q.; Cai, S.; Zhang, J. The Biodegradation Pathway of Triethylamine and Its Biodegradation by Immobilized Arthrobacter Protophormiae Cells. J. Hazard. Mater. 2011, 186, 59– 66,  DOI: 10.1016/j.jhazmat.2010.10.007
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      The biodegradation pathway of triethylamine and its biodegradation by immobilized Arthrobacter protophormiae cells
      Cai, Tianming; Chen, Liwei; Ren, Qian; Cai, Shu; Zhang, Jin
      Journal of Hazardous Materials (2011), 186 (1), 59-66CODEN: JHMAD9; ISSN:0304-3894. (Elsevier B.V.)
      A bacterial strain named R4 was isolated from a wastewater treatment tank contg. triethylamine (TEA) as the sole source of C and N. Strain R4 was identified as Arthrobacter protophormiae based on 16S rRNA gene sequence anal. and morphol. and physiol. properties. The optimal pH, temp. and concn. of NaCl for TEA degrdn. by strain R4 were 7.0, 30° and 0.5%, resp. Strain R4 could completely degrade 100 mg/L TEA to ammonia in 32 h, and could also effectively degrade diethylamine (DEA) and ethylamine (EA) to ammonia. The degrdn. of TEA was strongly inhibited by Cu2+, Mn2+, Zn2+, Co2+, Ni2+ and Ag+ (1.0mM). Addn. of either SO42- or NH4+ reduced the degrdn. efficiency of TEA by strain R4 to a certain extent. The inhibition became significant when the concn. of SO42- and NH4+ reached 11mM and 30 mM, resp. Cell-free exts. prepd. from cells grown in TEA exhibited TEA monooxygenase, DEA monooxygenase and EA monooxygenase activity. We propose the metabolic pathway of TEA degrdn. in strain R4. The efficiency of TEA removal by immobilized cells of strain R4 was equiv. to that of free cells. The immobilized cells could be reused without redn. in their ability to degrade TEA.
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    58. 58
      Lak, A.; Cassani, M.; Mai, B. T.; Winckelmans, N.; Cabrera, D.; Sadrollahi, E.; Marras, S.; Remmer, H.; Fiorito, S.; Cremades-Jimeno, L.; Litterst, F. J.; Ludwig, F.; Manna, L.; Teran, F. J.; Bals, S.; Pellegrino, T. Fe2+ Deficiencies, Feo Subdomains, and Structural Defects Favor Magnetic Hyperthermia Performance of Iron Oxide Nanocubes into Intracellular Environment. Nano Lett. 2018, 18, 6856– 6866,  DOI: 10.1021/acs.nanolett.8b02722
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      58
      Fe2+ Deficiencies, FeO Subdomains, and Structural Defects Favor Magnetic Hyperthermia Performance of Iron Oxide Nanocubes into Intracellular Environment
      Lak, Aidin; Cassani, Marco; Mai, Binh T.; Winckelmans, Naomi; Cabrera, David; Sadrollahi, Elaheh; Marras, Sergio; Remmer, Hilke; Fiorito, Sergio; Cremades-Jimeno, Lucia; Litterst, Fred Jochen; Ludwig, Frank; Manna, Liberato; Teran, Francisco J.; Bals, Sara; Pellegrino, Teresa
      Nano Letters (2018), 18 (11), 6856-6866CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
      Herein, by studying a stepwise phase transformation of 23 nm FeO-Fe3O4 core-shell nanocubes into Fe3O4, we identify a compn. at which the magnetic heating performance of the nanocubes is not affected by the medium viscosity and aggregation. Structural and magnetic characterizations reveal the transformation of the FeO-Fe3O4 nanocubes from having stoichiometric phase compns. into Fe2+-deficient Fe3O4 phases. The resultant nanocubes contain tiny compressed and randomly distributed FeO subdomains as well as structural defects. This phase transformation causes a 10-fold increase in the magnetic losses of the nanocubes, which remain exceptionally insensitive to the medium viscosity as well as aggregation unlike similarly sized single-phase magnetite nanocubes. We observe that the dominant relaxation mechanism switches from N´eel in fresh core-shell nanocubes to Brownian in partially oxidized nanocubes and once again to N´eel in completely treated nanocubes. The Fe2+ deficiencies and structural defects appear to reduce the magnetic energy barrier and anisotropy field, thereby driving the overall relaxation into N´eel process. The magnetic losses of these nanoparticles remain unchanged through a progressive internalization/assocn. to ovarian cancer cells. Moreover, the particles induce a significant cell death after being exposed to hyperthermia treatment. Here, we present the largest heating performance that has been reported to date for 23 nm iron oxide nanoparticles under intracellular conditions. Our findings clearly demonstrate the pos. impacts of the Fe2+ deficiencies and structural defects in the Fe3O4 structure on the heating performance into intracellular environment.
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    59. 59
      Serantes, D.; Simeonidis, K.; Angelakeris, M.; Chubykalo-Fesenko, O.; Marciello, M.; Morales, M. D. P.; Baldomir, D.; Martinez-Boubeta, C. Multiplying Magnetic Hyperthermia Response by Nanoparticle Assembling. J. Phys. Chem. C 2014, 118, 5927– 5934,  DOI: 10.1021/jp410717m
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      59
      Multiplying Magnetic Hyperthermia Response by Nanoparticle Assembling
      Serantes, David; Simeonidis, Konstantinos; Angelakeris, Makis; Chubykalo-Fesenko, Oksana; Marciello, Marzia; Morales, Maria del Puerto; Baldomir, Daniel; Martinez-Boubeta, Carlos
      Journal of Physical Chemistry C (2014), 118 (11), 5927-5934CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
      The oriented attachment of magnetic nanoparticles is recognized as an important pathway in the magnetic-hyperthermia cancer treatment roadmap, thus, understanding the phys. origin of their enhanced heating properties is a crucial task for the development of optimized application schemes. Here, we present a detailed theor. anal. of the hysteresis losses in dipolar-coupled magnetic nanoparticle assemblies as a function of both the geometry and length of the array, and of the orientation of the particles' magnetic anisotropy. Our results suggest that the chain-like arrangement biomimicking magnetotactic bacteria has the superior heating performance, increasing more than 5 times in comparison with the randomly distributed system when aligned with the magnetic field. The size of the chains and the anisotropy of the particles can be correlated with the applied magnetic field in order to have optimum conditions for heat dissipation. Our exptl. calorimetrical measurements performed in aq. and agar gel suspensions of 44 nm magnetite nanoparticles at different densities, and oriented in a magnetic field, unambiguously demonstrate the important role of chain alignment on the heating efficiency. In low agar viscosity, similar to those of common biol. media, the initial orientation of the chains plays a minor role in the enhanced heating capacity while at high agar viscosity, chains aligned along the applied magnetic field show the max. heating. This knowledge opens new perspectives for improved handling of magnetic hyperthermia agents, an alternative to conventional cancer therapies.
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    60. 60
      Torres, T. E.; Lima, E.; Calatayud, M. P.; Sanz, B.; Ibarra, A.; Fernández-Pacheco, R.; Mayoral, A.; Marquina, C.; Ibarra, M. R.; Goya, G. F. The Relevance of Brownian Relaxation as Power Absorption Mechanism in Magnetic Hyperthermia. Sci. Rep. 2019, 9, 3992,  DOI: 10.1038/s41598-019-40341-y
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      60
      The relevance of Brownian relaxation as power absorption mechanism in Magnetic Hyperthermia
      Torres Teobaldo E; Calatayud M Pilar; Sanz Beatriz; Ibarra Alfonso; Fernandez-Pacheco Rodrigo; Ibarra M Ricardo; Goya Gerardo F; Torres Teobaldo E; Ibarra Alfonso; Fernandez-Pacheco Rodrigo; Ibarra M Ricardo; Lima Enio Jr; Mayoral Alvaro; Marquina Clara; Ibarra M Ricardo; Goya Gerardo F; Marquina Clara
      Scientific reports (2019), 9 (1), 3992 ISSN:.
      The Linear Response Theory (LRT) is a widely accepted framework to analyze the power absorption of magnetic nanoparticles for magnetic fluid hyperthermia. Its validity is restricted to low applied fields and/or to highly anisotropic magnetic nanoparticles. Here, we present a systematic experimental analysis and numerical calculations of the specific power absorption for highly anisotropic cobalt ferrite (CoFe2O4) magnetic nanoparticles with different average sizes and in different viscous media. The predominance of Brownian relaxation as the origin of the magnetic losses in these particles is established, and the changes of the Specific Power Absorption (SPA) with the viscosity of the carrier liquid are consistent with the LRT approximation. The impact of viscosity on SPA is relevant for the design of MNPs to heat the intracellular medium during in vitro and in vivo experiments. The combined numerical and experimental analyses presented here shed light on the underlying mechanisms that make highly anisotropic MNPs unsuitable for magnetic hyperthermia.
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      Chabner, B. A.; Roberts, T. G. Chemotherapy and the War on Cancer. Nat. Rev. Cancer 2005, 5, 65– 72,  DOI: 10.1038/nrc1529
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      Chemotherapy and the war on cancer
      Chabner, Bruce A.; Roberts, Thomas G.
      Nature Reviews Cancer (2005), 5 (1), 65-72CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)
      The era of chemotherapy began in the 1940s with the first uses of nitrogen mustards and antifolate drugs. Cancer drug development since then has transformed from a low-budget, government-supported research effort to a high-stakes, multi-billion dollar industry. The targeted-therapy revolution has arrived, but the principles and limitations of chemotherapy discovered by the early researchers still apply. This article chronicles the history of modern chemotherapy and identifies remaining challenges for the next generation of researchers.
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