Thermo-responsive self-immolative nanoassemblies: Direct and indirect triggering

A thermo-responsive end-cap based on a retro-Diels-Alder and subsequent furan elimination reaction was developed. It was used to cap poly(ethyl glyoxylate), allowing end-to-end depolymerization upon thermal triggering. Using block copolymers, thermo-responsive micelles and vesicles were prepared and shown to disassemble upon heating. Thermal degradation could also be triggered indirectly by magnetic field hyperthermia after incorporation of iron oxide nanoparticles into the assemblies

Thermosensitive polymer-grafted iron oxide nanoparticles studied by in situ dynamic light backscattering under magnetic hyperthermia

© 2015 IOP Publishing Ltd. Thermometry at the nanoscale is an emerging area fostered by intensive research on nanoparticles (NPs) that are capable of converting electromagnetic waves into heat. Recent results suggest that stationary gradients can be maintained between the surface of NPs and the bulk solvent, a phenomenon sometimes referred to as \u27cold hyperthermia\u27. However, the measurement of such highly localized temperatures is particularly challenging. We describe here a new approach to probing the temperature at the surface of iron oxide NPs and enhancing the understanding of this phenomenon. This approach involves the grafting of thermosensitive polymer chains to the NP surface followed by the measurement of macroscopic properties of the resulting NP suspension and comparison to a calibration curve built up by macroscopic heating. Superparamagnetic iron oxide NPs were prepared by the coprecipitation of ferrous and ferric salts and functionalized with amines, then azides using a sol-gel route followed by a dehydrative coupling reaction. Thermosensitive poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) with an alkyne end-group was synthesized by controlled radical polymerization and was grafted using a copper assisted azide-alkyne cycloaddition reaction. Measurement of the colloidal properties by dynamic light scattering (DLS) indicated that the thermosensitive NPs exhibited changes in their Zeta potential and hydrodynamic diameter as a function of pH and temperature due to the grafted PDMAEMA chains. These changes were accompanied by changes in the relaxivities of the NPs, suggesting application as thermosensitive contrast agents for magnetic resonance imaging (MRI). In addition, a new fibre-based backscattering setup enabled positioning of the DLS remote-head as close as possible to the coil of a magnetic heating inductor to afford in situ probing of the backscattered light intensity, hydrodynamic diameter, and temperature. This approach provides a promising platform for estimating the response of magnetic NPs to application of a radiofrequency magnetic field or for understanding the behaviour of other thermogenic NPs

Synthesis of magnetic and thermosensitive iron oxide based nanoparticles for biomedical applications

Cette thèse présente le développement de nanoparticules hybrides avec un coeur inorganique et une couronne organique pour des applications médicales. Des nanoparticules d’oxyde de fer ont été obtenues par synthèse polyol, en contrôlant leurs cristallinités, leurs morphologies (monocoeur ou multicoeur) et leurs tailles (de 4 à 37 nm). Leurs propriétés ont été évaluées et comparées pour de possibles applications théranostiques : en thérapie pour le traitement du cancer par hyperthermie magnétique, pour le diagnostic en tant qu’agents de contraste pour l’IRM. Les surfaces des nanoparticules ont été modifiées par greffage de polymères/polypeptides pour apporter de la stabilité en milieux biologiques et de nouvelles fonctionnalités. Le poly(éthylène glycol) (PEG) a été greffé pour ses propriétés de furtivité, le poly(2-dimethylaminoethyl methacrylate) (PDMAEMA) et des polypeptides dérivés de l’élastine (ELPs) pour leurs propriétés thermosensibles, et la sonde fluorescente DY700 pour permettre le suivi des nanoparticules in vitro et in vivo. Les propriétés magnétiques et thermosensibles de ces nanoparticules coeur-couronne ont été étudiées avec un instrument unique combinant l’hyperthermie magnétique et un système de diffusion dynamique de la lumière. Ainsi, les variations de température, de diamètre et d’intensité diffusée ont pu être mesurées simultanément. Les propriétés de nanoparticules monocoeur et multicoeur greffées avec du PEG, et des nanoparticules monocoeur greffées avec un ELP contenant un peptide pénétrant ont d’abord été évaluées in vitro. Leurs internalisations dans des cellules de tumeur cérébrale humaine (glioblastome) ont permis d’étudier leurs cytotoxicités après traitement par hyperthermie magnétique, et ont montré une baisse de viabilité cellulaire jusqu’à 90 %. In vivo, l’injection intraveineuse de ces nanoparticules dans des souris a abouti à une accumulation dans les tumeurs. L’injection intratumorale suivie du traitement par hyperthermie magnétique a conduit à des élévations de température locales d’environ 10 °C, avec un effet significatif sur l’activité des tumeurs.This thesis reports the development of hybrid nanoparticles made of an inorganic iron oxide core and an organic shell for medical applications. Iron oxide nanoparticles (IONPs) were produced by the polyol pathway, leading to a good control over their crystallinity and morphology (monocore or multicore). IONPs with diameters in the range of 4 to 37 nm were produced. Their properties as MRI contrast agents were assessed and compared, for possible theranostic applications. They can be used for treating cancer by magnetic hyperthermia, and as contrast agents for MR imaging. The surface of the IONPs was modified to bring stability in biological conditions, as well as new functionalities. Poly(ethylene glycol) was grafted for its stealth property, poly(2-dimethylaminoethyl methacrylate) (PDMAEMA) and elastin-like polypeptides (ELPs) for their thermosensitive capabilities, and a DY700 fluorescent probe was grafted for tracking nanoparticles in vitro and in vivo. The magnetic and thermosensitive properties of the nanoparticles were studied using a unique set-up combining magnetic hyperthermia with dynamic-light scattering. This set-up allowed measuring the elevations of temperature of the samples as well as variations in diameter and backscattered intensity. Monocore and multicore IONPs grafted with PEG, and monore IONPs grafted with a diblock ELP were tested in vitro. Their interactions with glioblastoma cells were studied, from the internalization pathway inside the cells to their cytotoxic effect (up to 90 %) under magnetic hyperthermia. In vivo, nanoparticles intravenously injected in mice accumulated in the tumors. Intratumoral administration followed by magnetic hyperthermia treatment led to elevations of temperature of up to 10 °C, with a significant effect on the tumor activity

Synthesis of magnetic and thermosensitive iron oxide based nanoparticles for biomedical applications

Cette thèse présente le développement de nanoparticules hybrides avec un coeur inorganique et une couronne organique pour des applications médicales. Des nanoparticules d’oxyde de fer ont été obtenues par synthèse polyol, en contrôlant leurs cristallinités, leurs morphologies (monocoeur ou multicoeur) et leurs tailles (de 4 à 37 nm). Leurs propriétés ont été évaluées et comparées pour de possibles applications théranostiques : en thérapie pour le traitement du cancer par hyperthermie magnétique, pour le diagnostic en tant qu’agents de contraste pour l’IRM. Les surfaces des nanoparticules ont été modifiées par greffage de polymères/polypeptides pour apporter de la stabilité en milieux biologiques et de nouvelles fonctionnalités. Le poly(éthylène glycol) (PEG) a été greffé pour ses propriétés de furtivité, le poly(2-dimethylaminoethyl methacrylate) (PDMAEMA) et des polypeptides dérivés de l’élastine (ELPs) pour leurs propriétés thermosensibles, et la sonde fluorescente DY700 pour permettre le suivi des nanoparticules in vitro et in vivo. Les propriétés magnétiques et thermosensibles de ces nanoparticules coeur-couronne ont été étudiées avec un instrument unique combinant l’hyperthermie magnétique et un système de diffusion dynamique de la lumière. Ainsi, les variations de température, de diamètre et d’intensité diffusée ont pu être mesurées simultanément. Les propriétés de nanoparticules monocoeur et multicoeur greffées avec du PEG, et des nanoparticules monocoeur greffées avec un ELP contenant un peptide pénétrant ont d’abord été évaluées in vitro. Leurs internalisations dans des cellules de tumeur cérébrale humaine (glioblastome) ont permis d’étudier leurs cytotoxicités après traitement par hyperthermie magnétique, et ont montré une baisse de viabilité cellulaire jusqu’à 90 %. In vivo, l’injection intraveineuse de ces nanoparticules dans des souris a abouti à une accumulation dans les tumeurs. L’injection intratumorale suivie du traitement par hyperthermie magnétique a conduit à des élévations de température locales d’environ 10 °C, avec un effet significatif sur l’activité des tumeurs.This thesis reports the development of hybrid nanoparticles made of an inorganic iron oxide core and an organic shell for medical applications. Iron oxide nanoparticles (IONPs) were produced by the polyol pathway, leading to a good control over their crystallinity and morphology (monocore or multicore). IONPs with diameters in the range of 4 to 37 nm were produced. Their properties as MRI contrast agents were assessed and compared, for possible theranostic applications. They can be used for treating cancer by magnetic hyperthermia, and as contrast agents for MR imaging. The surface of the IONPs was modified to bring stability in biological conditions, as well as new functionalities. Poly(ethylene glycol) was grafted for its stealth property, poly(2-dimethylaminoethyl methacrylate) (PDMAEMA) and elastin-like polypeptides (ELPs) for their thermosensitive capabilities, and a DY700 fluorescent probe was grafted for tracking nanoparticles in vitro and in vivo. The magnetic and thermosensitive properties of the nanoparticles were studied using a unique set-up combining magnetic hyperthermia with dynamic-light scattering. This set-up allowed measuring the elevations of temperature of the samples as well as variations in diameter and backscattered intensity. Monocore and multicore IONPs grafted with PEG, and monore IONPs grafted with a diblock ELP were tested in vitro. Their interactions with glioblastoma cells were studied, from the internalization pathway inside the cells to their cytotoxic effect (up to 90 %) under magnetic hyperthermia. In vivo, nanoparticles intravenously injected in mice accumulated in the tumors. Intratumoral administration followed by magnetic hyperthermia treatment led to elevations of temperature of up to 10 °C, with a significant effect on the tumor activity

Synthèse de nanoparticules magnétiques et thermosensibles à base d'oxyde de fer pour des applications biomédicales

This thesis reports the development of hybrid nanoparticles made of an inorganic iron oxide core and an organic shell for medical applications. Iron oxide nanoparticles (IONPs) were produced by the polyol pathway, leading to a good control over their crystallinity and morphology (monocore or multicore). IONPs with diameters in the range of 4 to 37 nm were produced. Their properties as MRI contrast agents were assessed and compared, for possible theranostic applications. They can be used for treating cancer by magnetic hyperthermia, and as contrast agents for MR imaging. The surface of the IONPs was modified to bring stability in biological conditions, as well as new functionalities. Poly(ethylene glycol) was grafted for its stealth property, poly(2-dimethylaminoethyl methacrylate) (PDMAEMA) and elastin-like polypeptides (ELPs) for their thermosensitive capabilities, and a DY700 fluorescent probe was grafted for tracking nanoparticles in vitro and in vivo. The magnetic and thermosensitive properties of the nanoparticles were studied using a unique set-up combining magnetic hyperthermia with dynamic-light scattering. This set-up allowed measuring the elevations of temperature of the samples as well as variations in diameter and backscattered intensity. Monocore and multicore IONPs grafted with PEG, and monore IONPs grafted with a diblock ELP were tested in vitro. Their interactions with glioblastoma cells were studied, from the internalization pathway inside the cells to their cytotoxic effect (up to 90 %) under magnetic hyperthermia. In vivo, nanoparticles intravenously injected in mice accumulated in the tumors. Intratumoral administration followed by magnetic hyperthermia treatment led to elevations of temperature of up to 10 °C, with a significant effect on the tumor activity.Cette thèse présente le développement de nanoparticules hybrides avec un coeur inorganique et une couronne organique pour des applications médicales. Des nanoparticules d’oxyde de fer ont été obtenues par synthèse polyol, en contrôlant leurs cristallinités, leurs morphologies (monocoeur ou multicoeur) et leurs tailles (de 4 à 37 nm). Leurs propriétés ont été évaluées et comparées pour de possibles applications théranostiques : en thérapie pour le traitement du cancer par hyperthermie magnétique, pour le diagnostic en tant qu’agents de contraste pour l’IRM. Les surfaces des nanoparticules ont été modifiées par greffage de polymères/polypeptides pour apporter de la stabilité en milieux biologiques et de nouvelles fonctionnalités. Le poly(éthylène glycol) (PEG) a été greffé pour ses propriétés de furtivité, le poly(2-dimethylaminoethyl methacrylate) (PDMAEMA) et des polypeptides dérivés de l’élastine (ELPs) pour leurs propriétés thermosensibles, et la sonde fluorescente DY700 pour permettre le suivi des nanoparticules in vitro et in vivo. Les propriétés magnétiques et thermosensibles de ces nanoparticules coeur-couronne ont été étudiées avec un instrument unique combinant l’hyperthermie magnétique et un système de diffusion dynamique de la lumière. Ainsi, les variations de température, de diamètre et d’intensité diffusée ont pu être mesurées simultanément. Les propriétés de nanoparticules monocoeur et multicoeur greffées avec du PEG, et des nanoparticules monocoeur greffées avec un ELP contenant un peptide pénétrant ont d’abord été évaluées in vitro. Leurs internalisations dans des cellules de tumeur cérébrale humaine (glioblastome) ont permis d’étudier leurs cytotoxicités après traitement par hyperthermie magnétique, et ont montré une baisse de viabilité cellulaire jusqu’à 90 %. In vivo, l’injection intraveineuse de ces nanoparticules dans des souris a abouti à une accumulation dans les tumeurs. L’injection intratumorale suivie du traitement par hyperthermie magnétique a conduit à des élévations de température locales d’environ 10 °C, avec un effet significatif sur l’activité des tumeurs

Selective Release of Doxorubicin Using PEG-Grafted Iron Oxide Nanoparticles via a Retro-Diels-Alder Reaction

Chemistry, Department o

Kinetics of aggregation and magnetic separation of multicore iron oxide nanoparticles: effect of the grafted layer thickness

Magnetic microbeads are commonly used in immunoassays to detect trace levels of antigens. Despite weaker magnetic attraction, we aim at developing efficient magnetic capture of multi-core magnetic nanoparticles (MNP) also called nanoflowers,[1] of outer diameter 30-60 nm, by using moderate magnetic field strengths. Recent work by some of us showed that magnetic interactions between MNPs of this size can still be strong enough to induce a reversible phase separation in the presence of a magnetic field B as weak as 10 mT.[2] During this phase separation, MNPs are gathered into micron-sized drop-like aggregates whose magnetic interaction with the applied field is much stronger than between individual nanoparticles and larger than thermal agitation kBT. These fluid-like aggregates can then be separated from the solvent much more easily than single MNPs. Moreover, it is beneficial in continuous filtration to assemble the aggregates well before they are captured by magnetized collectors, by conveying the MNP suspension to the micro-filter across a microchannel submitted to a uniform external magnetic field H0. This communication establishes the mechanisms of multi-core MNP capture in microfluidic channels under magnetic and flow fields, and presents a phase diagram in terms of Mason number, dipolar coupling constant, and thickness of the organic coating wrapping the multi-core MNPs: short citrate molecules or PEG chains.[3][1] H. Ezzaier, J. Alves Marins, S. Schaub, B. H.Amara, P. Kuzhir, J. Mag. Mag. Mat. 2017 In Press[2] G Hemery, A Keyes, E Garaio, I Rodrigo, J A Garcia, F Plazaola, E Garanger, O Sandre, Inorg. Chem. 2017, 56, 8232[3] G. Hemery, C. Genevois, F. Couillaud, S. Lacomme, E. Gontier, E. Ibarboure, S. Lecommandoux, E. Garanger, O. Sandre, Mol. Sys. Des. Eng. 2017, 2, 629-639

Fundamentals and advances in magnetic hyperthermia

Nowadays, magnetic hyperthermia constitutes a complementary approach to cancer treatment. The use of magnetic particles as heating mediators, proposed in the 1950s, provides a novel strategy for improving tumor treatment and, consequently, patient's quality of life. This review reports a broad overview about several aspects of magnetic hyperthermia addressing new perspectives and the progress on relevant features such as the ad hoc preparation of magnetic nanoparticles, physical modeling of magnetic heating, methods to determine the heat dissipation power of magnetic colloids including the development of experimental apparatus and the influence of biological matrices on the heating efficiency.Multifunctional Nanoparticles for Magnetic Hyperthermia and Indirect Radiation Therap

Monocore vs multicore magnetic iron oxide nanoparticles: uptake by glioblastoma cells and efficiency for magnetic hyperthermia

PEGylated magnetic iron oxide nanoparticles (IONPs) were synthesised with the aim to provide proof of concept results of remote cancer cell killing by magnetic fluid hyperthermia. The IONPs were produced by the polyol synthetic route also called “forced hydrolysis pathway” yielding highly superparamagnetic, readily-dispersible, and biocompatible IONPs. As shown previously, adjusting parameters of the reaction led to either monocore or multicore IONPs, with on-demand morphology and magnetic properties. Polyethylene glycol (PEG) was grafted onto the nanoparticles in a single final step, using a phosphonic acid-terminated PEG synthesised separately, a strategy named “convergent”. The magnetic properties of the IONPs were preserved in physiological media thanks to this biocompatible shell. The interaction of the PEGylated IONPs with a glioblastoma cell line was studied, from the stability of IONPs in appropriate cell culture medium to the remotely magnetically triggered cell death. Cellular internalisation of the IONPs was studied, along with their fate after application of an alternating magnetic field (AMF). This investigation highlights the superior efficiency of multicore (nanoflowers) vs monocore (nanospheres) IONPs for magnetic hyperthermia, leading to 80 % cancer cells death in medically translatable conditions.Magnéto-Chimiothérapie : Modélisation de la Délivrance Induite par Champ Magnétique Radiofréquence d'Anticancéreux par des Nano-Vésicules Polymères et Suivi par IRM d'un Modèle de GlioblastomeDéveloppment d'une infrastructure française distribuée coordonnéeMultifunctional Nanoparticles for Magnetic Hyperthermia and Indirect Radiation Therap

Synthesis and self-assembly of Xylan-based amphiphiles: from bio-based vesicles to antifungal properties

This work aims at designing functional biomaterials through selective chemical modification of xylan from beechwood. Acidic hydrolysis of xylan leaded to well-defined oligomers with an average of six xylose units per chain and with an aldehyde group at the reductive end. Reductive amination was performed on this aldehyde end-group to introduce an azide reactive group. 'Click chemistry' was then applied to couple these hydrophilic xylans moieties with different hydrophobic fatty acid methyl esters that were previously functionalized with complementary alkyne functions. The resulting amphiphilic bio-based conjugates were then self-assembled using three different methods, namely direct solubilization, thin-film rehydration/extrusion and microfluidics. Well -defined micelles and vesicles were obtained and their high loading capacity with propiconazole as an antifungal active molecule was shown. The resulting vesicles loaded with propiconazole in a microfluidic process, proved to significantly improve the antifungal activity of propiconazole, demonstrating the high potential of such xylan-based amphiphiles.Plateforme d’Innovation « Forêt-Bois-Fibre-Biomasse du Futur