Projet de thèse en Chimie
Sous la direction de Ruxandra Gref et de Christian Serre.
Thèses en préparation à Paris Saclay , dans le cadre de École doctorale Sciences chimiques : molécules, matériaux, instrumentation et biosystèmes (Orsay, Essonne ; 2015-....) , en partenariat avec Institut des Sciences Moléculaires d'Orsay (laboratoire) , Biophysique et Biophotonique (equipe de recherche) et de Université Paris-Sud (établissement de préparation de la thèse) depuis le 10-11-2017 .
L'objectif de ce projet est l'étude du mécanisme de dégradation de certains MOFs dans le domaine biomédical (carboxylates de fer ou de zirconium, azolates de cuivre ou de zinc). En plus de la structure ou de la composition, d'autres paramètres seront étudiés tels que la taille des particules (nano ou micro, de 50-100 nm jusqu' à quelques dizaines de microns), ou la présence de médicaments dans les pores. Les médicaments pourront être coordonnés aux sites métalliques (e.g. Gemcitabine phosphate) ou être hydrophobes (e.g. Doxorubicin) ce qui aura un impact sur la cinétique de dégradation. L'examen de ces paramètres est très important pour la compréhension et donc pour le contrôle des mécanismes de libération des médicaments.
A comprehensive study of the erosion mechanism of porous hybrid particles
Research in the field of drug delivery has witnessed tremendous progress in recent years due unlimited potential to improve human health. Nanotechnology provides opportunities to manipulate and organize matter at the nanometer scale to elaborate reservoirs for the controlled release of drugs at targeted sites in the body. Metal Organic Frameworks (MOFs) have recently emerged as crystalline porous materials of interest for biomedical applications, with potential applications in drug delivery and imaging. Their high porosity, large surface areas and versatility in terms of composition and functionalities make the MOFs particularly appealing for the incorporation of high drug payloads (Horcajada et al. Nature Mater. 2010). Many efforts have been carried out to synthesize biocompatible MOFs using endogenous linkers or pharmaceutical acceptable excipients. Two of the teams involved in this project have pioneered the development of nanoscale MOFs (nanoMOFs) for biomedical applications. Drugs were successfully entrapped in the cages of these versatile materials and were released in a controlled manner (Horcajada Nat Mat 2010). MOFs have been shown to load unprecedented amounts (within the 20-140 wt% range) of a series of drugs able to efficiently penetrate the porous MOF structures. More particularly, iron(III) trimesate MIL-100 and iron(III) terephtalate MIL-101 (MIL stands for Materials of Institut Lavoisier) are considered among the most efficient materials as drug delivery systems because of their large pore sizes (29 and 34 Å for MIL-100 and MIL-101, respectively). The toxicity of nanoMOFs has been thoroughly investigated both in vitro and in vivo (Baati et al., Chemical Science). High doses of nanoparticles of porous iron(III) carboxylate MOFs were intravenously administered in rats and their biodistribution, metabolism and excretion were determined. All studied parameters (serum, enzymatic, histological, etc.) were in agreement with a low acute toxicity. It was evidenced that the MOFs were degraded and that their degradation products were excreted in urine or feces without metabolization nor induced toxic effects. Besides, it was clearly shown that degradation of MOFs was closely related to drug release. The porous matrices degraded in biological media, losing their crystalline supramolecular structures. Drugs leak out from this more and more porous matrices which eventually break down. In conclusion, numerous publications in the field demonstrated that MOF degradation plays a crucial role in biological fate and drug release, two key factors in the design of drug carriers. However, little is known upon the degradation mechanism of MOFs. The recent observation of the degradation of individual large MOF particles showed that their core remained intact whereas a highly porous and inorganic shell was formed. During degradation in phosphate buffers or cell culture media, the MOF constitutive ligands were released leaving a shell probably made of iron oxides or iron phosphates. Tomography will be a tool of choice to investigate structural changes of particles of 50 µm or more. MIL-100 particles are expected to degrade within days, whereas MIL-101 ones degrade more readily within minutes in aqueous media. The methodology developed here could be used to study the degradation of a large family of MOFs. This interdisciplinary project will be carried on in close collaboration between teams in ISMO, ENS and Soleil. Information generated in this project would greatly impact the further development of MOFs for biomedical applications.