Recent insights in magnetic hyperthermia: From the “hot-spot” effect for local delivery to combined magneto-photo-thermia using magneto-plasmonic hybrids

International audienceMagnetic hyperthermia which exploits the heat generated by magnetic nanoparticles (MNPs) when exposed to an alternative magnetic field (AMF) is now in clinical trials for the treatment of cancers. However, this thermal therapy requires a high amount of MNPs in the tumor to be efficient. On the contrary the hot spot local effect refers to the use of specific temperature 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 experimental proofs of the local temperature increase are first discussed leading to a good estimation of the temperature 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

Magnetic protein imprinted polymer nanoparticles : from synthesis to applications in nanomedicine

Cette thèse porte sur le développement de nanoparticules magnétiques hybrides pour la nanomédecine. Un enjeu majeur est de proposer des solutions innovantes dans le traitement et/ou le diagnostic de certaines pathologies, comme les cancers. Les nanoparticules magnétiques possèdent des propriétés extrêmement intéressantes pour la nanomédecine. Elles peuvent servir à guider magnétiquement un vecteur vers une cible ou à chauffer localement cette cible lorsqu’elles sont soumises à un champ magnétique alternatif. Par ailleurs, l’utilisation de polymères à empreintes de protéines peut permettre de cibler des protéines d’intérêt. L’idée ici est donc de coupler des nanoparticules magnétiques et des polymères à empreintes de protéines (PEP) afin de cibler, détecter et traiter des cellules d’intérêt. Les nano-objets γ-Fe2O3@PEP sont synthétisés en polymérisant un polyacrylamide autour de protéines servant de gabarit, telles que la protéine fluorescente verte ou le complexe de différentiation 44. Les objets obtenus sont composés pour 10 à 30% de PEP, selon la méthode de synthèse. Un ciblage efficace de cellules exprimant ces protéines d’intérêt a été mis en œuvre. Sous champ magnétique alternatif, les protéines sont dénaturées mais les nano-objets γ-Fe2O3@PEP ne se détachent pas des cellules, et seront donc à terme internalisés. Une étude approfondie a montré une absence de toxicité aigüe des objets hybrides, et leur métabolisation dans les lysosomes. Les propriétés de ciblage et d’hyperthermie de γ-Fe2O3@PEP en font donc un bon candidat pour détecter et ralentir le développement de métastases cancéreuses.This thesis focuses on the development of hybrid magnetic nanoparticles for nanomedicine. A major challenge is to propose innovative solutions in the treatment and/or diagnosis of some pathologies, such as cancers. Magnetic nanoparticles are interesting for nanomedicine because they can be employed to magnetically direct a vector toward a target, or locally heat this target when submitted to an alternating magnetic field. Moreover, protein imprinted polymers can be used to selectively target proteins of interest. Thus, the idea of this project is to bind magnetic nanoparticles and protein imprinted polymers (PIP), to propose a new system to target, detect and treat cells of interest. γ-Fe2O3@PIP hybrid nano-objects were synthesized through polymerization of polyacrylamide around template proteins, such as green fluorescent proteins or the glycoproteins CD44. PIP represent less than 30 % of final hybrid nano-objects, which have hydrodynamic diameters smaller than 400 nm, according to the synthetic pathway. Effective targeting of cells displaying these proteins of interest occurred while using γ-Fe2O3@PIP nano-objects. Under an alternating magnetic field, proteins are denatured thanks to magnetic hyperthermia. γ-Fe2O3@PIP particles will not detach themselves from the cell, and will thus be internalized. A further study denoted the absence of an acute cytotoxicity for hybrid nano-objects, which will be metabolized inside lysosomes. Targeting and magnetic hyperthermia properties of γ-Fe2O3@PIP make them ideal candidates to detect cancer metastasis and slow down their development

Protein Denaturation Through the Use of Magnetic Molecularly Imprinted Polymer Nanoparticles

The inhibition of the protein function for therapeutic applications remains challenging despite progress these past years. While the targeting application of molecularly imprinted polymer are in their infancy, no use was ever made of their magnetic hyperthermia properties to damage proteins when they are coupled to magnetic nanoparticles. Therefore, we have developed a facile and effective method to synthesize magnetic molecularly imprinted polymer nanoparticles using the green fluorescent protein (GFP) as the template, a bulk imprinting of proteins combined with a grafting approach onto maghemite nanoparticles. The hybrid material exhibits very high adsorption capacities and very strong affinity constants towards GFP. We show that the heat generated locally upon alternative magnetic field is responsible of the decrease of fluorescence intensity

Polymères à empreintes de protéines couplés à des nanoparticules magnétiques : de la synthèse aux applications en nanomédecine

This thesis focuses on the development of hybrid magnetic nanoparticles for nanomedicine. A major challenge is to propose innovative solutions in the treatment and/or diagnosis of some pathologies, such as cancers. Magnetic nanoparticles are interesting for nanomedicine because they can be employed to magnetically direct a vector toward a target, or locally heat this target when submitted to an alternating magnetic field. Moreover, protein imprinted polymers can be used to selectively target proteins of interest. Thus, the idea of this project is to bind magnetic nanoparticles and protein imprinted polymers (PIP), to propose a new system to target, detect and treat cells of interest. γ-Fe2O3@PIP hybrid nano-objects were synthesized through polymerization of polyacrylamide around template proteins, such as green fluorescent proteins or the glycoproteins CD44. PIP represent less than 30 % of final hybrid nano-objects, which have hydrodynamic diameters smaller than 400 nm, according to the synthetic pathway. Effective targeting of cells displaying these proteins of interest occurred while using γ-Fe2O3@PIP nano-objects. Under an alternating magnetic field, proteins are denatured thanks to magnetic hyperthermia. γ-Fe2O3@PIP particles will not detach themselves from the cell, and will thus be internalized. A further study denoted the absence of an acute cytotoxicity for hybrid nano-objects, which will be metabolized inside lysosomes. Targeting and magnetic hyperthermia properties of γ-Fe2O3@PIP make them ideal candidates to detect cancer metastasis and slow down their development.Cette thèse porte sur le développement de nanoparticules magnétiques hybrides pour la nanomédecine. Un enjeu majeur est de proposer des solutions innovantes dans le traitement et/ou le diagnostic de certaines pathologies, comme les cancers. Les nanoparticules magnétiques possèdent des propriétés extrêmement intéressantes pour la nanomédecine. Elles peuvent servir à guider magnétiquement un vecteur vers une cible ou à chauffer localement cette cible lorsqu’elles sont soumises à un champ magnétique alternatif. Par ailleurs, l’utilisation de polymères à empreintes de protéines peut permettre de cibler des protéines d’intérêt. L’idée ici est donc de coupler des nanoparticules magnétiques et des polymères à empreintes de protéines (PEP) afin de cibler, détecter et traiter des cellules d’intérêt. Les nano-objets γ-Fe2O3@PEP sont synthétisés en polymérisant un polyacrylamide autour de protéines servant de gabarit, telles que la protéine fluorescente verte ou le complexe de différentiation 44. Les objets obtenus sont composés pour 10 à 30% de PEP, selon la méthode de synthèse. Un ciblage efficace de cellules exprimant ces protéines d’intérêt a été mis en œuvre. Sous champ magnétique alternatif, les protéines sont dénaturées mais les nano-objets γ-Fe2O3@PEP ne se détachent pas des cellules, et seront donc à terme internalisés. Une étude approfondie a montré une absence de toxicité aigüe des objets hybrides, et leur métabolisation dans les lysosomes. Les propriétés de ciblage et d’hyperthermie de γ-Fe2O3@PEP en font donc un bon candidat pour détecter et ralentir le développement de métastases cancéreuses

Grain-boundary-induced melting in quenched polycrystalline monolayers

Melting in two dimensions can successfully be explained with the Kosterlitz-Thouless-Halperin-Nelson-Young (KTHNY) scenario which describes the formation of the high-symmetry phase with the thermal activation of topological defects within an (ideally) infinite monodomain. With all state variables being well defined, it should hold also as freezing scenario where oppositely charged topological defects annihilate. The Kibble-Zurek mechanism, on the other hand, shows that spontaneous symmetry breaking alongside a continuous phase transition cannot support an infinite monodomain but leads to polycrystallinity. For any nonzero cooling rate, critical fluctuations will be frozen out in the vicinity of the transition temperature. This leads to domains with different director of the broken symmetry, separated by a defect structure, e.g., grain boundaries in crystalline systems. After instantaneously quenching a colloidal monolayer from a polycrystalline to the isotropic fluid state, we show that such grain boundaries increase the probability for the formation of dislocations. In addition, we determine the temporal decay of defect core energies during the first few Brownian times after the quench. Despite the fact that the KTHNY scenario describes a continuous phase transition and phase equilibrium does not exist, melting in polycrystalline samples starts at grain boundaries similar to first-order phase transitions.publishe

Protein Denaturation Through the Use of Magnetic Molecularly Imprinted Polymer Nanoparticles

The inhibition of the protein function for therapeutic applications remains challenging despite progress these past years. While the targeting application of molecularly imprinted polymer are in their infancy, no use was ever made of their magnetic hyperthermia properties to damage proteins when they are coupled to magnetic nanoparticles. Therefore, we have developed a facile and effective method to synthesize magnetic molecularly imprinted polymer nanoparticles using the green fluorescent protein (GFP) as the template, a bulk imprinting of proteins combined with a grafting approach onto maghemite nanoparticles. The hybrid material exhibits very high adsorption capacities and very strong affinity constants towards GFP. We show that the heat generated locally upon alternative magnetic field is responsible of the decrease of fluorescence intensity

Biological Fate of Magnetic Protein-Specific Molecularly Imprinted Polymers: Toxicity and Degradation

International audienceMagnetic nanoparticles coated with protein-specific molecularly imprinted polymers (MIPs) are receiving increasing attention thanks to their binding abilities, robustness, and easy synthesis compared to their natural analogues also able to target proteins, such as antibodies or aptamers. Acting as tailor-made recognition systems, protein-specific MIPs can be used in many in vivo nanomedicine applications, such as targeted drug delivery, biosensing, and tissue engineering. Nonetheless, studies on their biocompatibility and long-term fate in biological environments are almost nonexistent, although these questions have to be addressed before considering clinical applications. To alleviate this lack of knowledge, we propose here to monitor the effect of a protein-specific MIP coating on the toxicity and biodegradation of magnetic iron oxide nanoparticles, both in a minimal aqueous degradation medium and in a model of cartilage tissue formed by differentiated human mesenchymal stem cells. Degradation of iron oxide nanoparticles with or without the polymer coating was monitored for a month by following their magnetic properties using vibrating sample magnetometry and their morphology by transmission electron microscopy. We showed that the MIP coating of magnetic iron oxide nanoparticles does not affect their biocompatibility or internalization inside cells. Remarkably, the imprinted polymer coating does not hinder the magnetic particle degradation but seems to slow it down, although this effect is more visible when degradation occurs in the buffer medium than in cells. Hence, the results presented in this paper are really encouraging and open up the way to future applications of MIP-coated nanoparticles into the clinic