Ttitre de la dissertation: MRI and fluorescence image-guided drug delivery by pH-sensitive polymer nanocarriers

Promoteurs de thèse: Madame Sophie LAURENT et Monsieur Olivier SANDRE

Résumé de la dissertation:Cancer remains a major cause of death in the world. A lot of efforts are thus made to diagnose it at an earlier stage and to treat it more efficiently. Indeed, the actually used treatments are invasive or lead to multi drug resistance by using several times chemotherapy techniques in a row, for example. Therefore, for several reasons there is a growing interest in nanomedicine, and more particularly on polymeric nano objects, to improve current treatments. They are indeed tunable, that is to say that they can be synthesized and tailored for the aimed application, they are able to encapsulate dyes and/or drugs within the vesicles or at their surface, they can be stimuli sensitive to perform on-site drug delivery, and so on. Moreover, the theragnostic area which combines drug delivery and imaging shows a growing interest thanks to imaging contrast agents encapsulated in the nanoobjects, allowing to follow them in vivo and to diagnose the evolution state of cancers. The most used imaging technique in hospital is magnetic resonance imaging (MRI). Nevertheless, this technique suffers from a lack in sensitivity that can be palliated by using contrast agents or bimodal systems. The most used contrast agents in clinic are based on gadolinium complexes. However, studies have proved that these contrast agents can lead to nephrogenic systemic fibrosis, more particularly for patients with kidney diseases as well as an accumulation in the brain after repeated injections. Herein, we have developed polymeric nano-objects, micelles and vesicles (also called polymersomes) which are made of a pH-sensitive polyester shell to obtain a controlled release of the encapsulated drug in the acidic tumoral environment. The polymer carrier is composed of an amphiphilic copolymer PEO-b-P(CL-co-LA) with a statistical hydrophobic block obtained by ring opening polymerization (ROP) of e-caprolactone and l-lactide (LLA). By adapting the self-assembly process, these nano-objects were shown to encapsulate doxorubicin, a well-known anti-cancer drug as well as fluorescent dyes, either rhodamine for cell studies or ZW800-1, a near infrared fluorophore derived from indocyanine green, which is already FDA approved as “contrastophore” in fluorescence live imaging (FLI). These nanosystems were characterized by different techniques able to evidence their structure, and then they were evaluated in vitro and in vivo.In the second part, to palliate to the issues induced by gadolinium complexes used in MRI, we have developed manganese complexes based on pyclen derivatives. The designed macrocyclic ligand was fully characterized and its efficiency in MRI was evaluated by different NMR techniques. Finally, their biodistribution, efficiency and impact in the organism were determined by in vivo tests. The manganese complexes showed an MRI contrasting efficiency close to that of gadolinium complexes. To improve it, it was envisaged to graft them on the surface of the nano-objects, which will modify the rotational correlation time of the complexes, and hence their efficacy. To perform this, a click chemistry reaction between the macrocycles and the nano-vesicles was planned, so that the Mn-complexes and the polymers have to be functionalized with the right chemical groups. Different strategies of synthesis were investigated to obtain the desired compounds.