Préparation de vésicules magnétiques pour le traitement anticancéreux par hyperthermie ou par photothérapie dynamique

Ce travail de thèse propose la préparation de Liposomes Ultra Magnétiques furtifs pour le traitement anticancéreux par thermothérapie et par photothérapie dynamique. Les caractérisations structurales et magnétiques prouvent que ces liposomes sont unilamellaires, de taille injectable et que leur contenu magnétique est extrêmement dense en nanoparticules d oxyde de fer. Cette dernière propriété est un atout majeur, permettant une excellente mobilité du vecteur ainsi qu une accumulation efficace in vivo, dans des tumeurs superficielles mais également dans des tissus profonds par application d un gradient de champ magnétique. Cette accumulation peut être suivie par IRM. La densité du cœur magnétique induit une capture cellulaire très importante des nanoparticules, propice à la dégradation ou à la destruction des cellules cancéreuses par hyperthermie. Les liposomes préparés sont également capables d accueillir une molécule photosensible dans leur membrane, leur conférant ainsi une fonctionnalité supplémentaire et exploitable pour le traitement par photothérapie dynamique. Ce manuscrit présente également une nouvelle stratégie de préparation de vésicules catanioniques magnétiques comme système modèle pour la vectorisation et la libération contrôlée de molécules hydrosolubles. Ces vésicules sont caractérisées par une décoration magnétique de leur surface, apportée par les nanoparticules d oxyde de fer. Par application d un champ magnétique radiofréquence, les résultats montrent qu il est possible d induire la libération d une molécule encapsulée dans le cœur des vésicules en provoquant la fusion des chaînes de tensioactifs des vésiculesThis work focuses on the preparation of stealth Ultra Magnetic Liposomes for cancer treatment by hyperthermia and photodynamic therapy. Structural and magnetic characterizations demonstrate that such liposomes are unilamellar, have a suitable size for injection and contain a remarkable magnetic charge. This last property is a major asset, which ensures an efficient magnetic mobility and an accumulation in vivo, not only in superficial tumors, but also in deep tissues, by applying a magnetic field gradient. The properties of iron oxide nanoparticles as a contrast agent enable the tracking of liposomes by MRI and the visualization of their accumulation in tumors. The iron content of liposomes induces a significant internalization of nanoparticles in cells, which could favor cell damaging or destruction by hyperthermia. A photosensitive molecule can be embedded in liposomes. This feature supplies an additional functionality to liposomes in photodynamic therapy for cancer treatment. These new liposomes, both photosensitive and magnetic, exhibit good preliminary in vitro abilities and are promising candidates for combined therapy. This manuscript also tackles the preparation of magnetic catanionic vesicles as a model system for vectorization and on-demand delivery of hydrophilic substances. These vesicles are characterized by surface decoration provided by iron oxide nanoparticles. By applying a radio-frequency oscillating magnetic field, it is possible to induce the delivery of the molecule by exploiting the melting of surfactants chainsPARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Magnetic Nanoparticles Create Hot Spots in Polymer Matrix for Controlled Drug Release

International audienceHerein, 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

size-sorted anionic iron oxide nanomagnets as colloidal mediators for magnetic hyperthermia

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Heating efficiency of magnetic nanoparticles decreases with gradual immobilization in hydrogels

Magnetic nanoparticles (MNP) applied in magnetic fluid hyperthermia cancer treatment interact with cancerous tissue in various ways. The impact of these interactions on MNP heating efficiency is hard to quantify and strongly depends on the MNP mobility inside the cancerous environment. There, this MNP mobility is inhibited by cell attachment and internalization. In this study, we model this impact and analyze the MNP heating under gradual immobilization of MNP in acrylamide hydrogels with tailored mesh size. Our results confirm a clear particle heating dependency on the state of immobilization of MNP. This state is related to the mean mesh size of the respective hydrogel. From this, the contributions of Brownian and Ned relaxation mechanisms to the overall particle heating are estimated. In fact, the heating efficiency decreases by up to 35% for the highest immobilization state of MNP. This result is discussed in the context of the field-dependent Brownian and Neel relaxation time, showing that the former significantly contributes to the heating efficiency even for small particles under the field parameters employed in this study

Novel Tools towards Magnetic Guidance of Neurite Growth: (I) Guidance of Magnetic Nanoparticles into Neurite Extensions of Induced Human Neurons and In Vitro Functionalization with RAS Regulating Proteins

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Ultrasmall superparamagnetic iron oxide nanoparticles coated with fucoidan for molecular MRI of intraluminal thrombus

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Liposomes for PET and MR imaging and for dual targeting (magnetic field/glucose moiety): synthesis, properties and in vivo studies

International audienceWe describe the potentiality of a new liposomal formulation enabling PET and MR imaging for cancer diagnosis. The bimodality is achieved by coupling a 68Ga-based radiotracer on the bilayer of ultra magnetic liposomes. In order to enhance the targeting properties obtained under a permanent magnetic field, a sugar moiety was added in the lipid formulation. Two new phospholipids were synthesized, one with a specific chelator of 68Ga (DSPE-PEG-NODAGA) and one with a glucose moiety (DSPE-PEG-Glucose). The liposomes were produced according to a fast and safe process, with a high radiolabeling yield. MR and PET imaging were performed on mice bearing human glioblastoma tumors (U87MG) after iv injection. The accumulation of the liposomes in solid tumor is evidenced by MR imaging and the amount is evaluated in vivo and ex vivo according to PET imaging. An efficient magnetic targeting is achieved with these new magnetic liposomes