Titre: New nitroxide-based nanoparticles: synthesis and evaluation of their use as MRI and EPR imaging contrast agents

Promoteurs de thèse: Mme Sophie LAURENT et Monsieur Dimitri Stanicki

Résumé de la dissertation: Medical imaging is a constantly expanding field of research that is now routinely used in the medical world. Indeed, the use and the development of contrast agents nowadays make it possible to obtain detailed information concerning many pathologies, which allows the improvement of their detection and treatment.MRI is one of the most widely used imaging techniques due to its high resolution and non-invasive nature, it commonly requires the injection of gadolinium complexes. However, their injection is questioned because it has been linked to a serious pathology, systemic nephrogenic fibrosis as well as to the accumulation of gadolinium in the brain of patients. Various compounds have since been studied as possible replacements, the structures of nitroxide-based nanoparticles being one of them. Indeed, such compounds have already been shown to lead to an increase in their ¹H relaxivity, as well as an improvement in their stability in a physiological medium thanks to their composition, giving them properties sought after for an application as contrast agents for MRI. First, as part of this work, the development of dendrimers functionalized by nitroxides was developed. Subsequently, various formulations for the incorporation of nitroxides, on the surface or in the core, of silica nanoparticles were studied. The grafting and encapsulation methods have been varied, as well as the structures used in order to obtain particles with various properties as well as to optimize the quantity of radicals introduced. The first objective was to define the ideal system by combining the maximum sensitivity in MRI with great stability in biological media. Their in vitro and in vivo characterizations were evaluated. The second objective of this part concerned the study of the factors influencing the increase in relaxivity observed thanks to the nanoparticle approach, because large variations are observed between the different studies carried out on this subject. This should improve the future development of such contrast agents for MRI.Another main application of nitroxides is their use as a contrast agent for EPR imaging. This technique allows the visualization of compounds with free electrons and is used in particular to perform oximetry measurements in vivo. However, it has not yet reached the stage of clinical studies for several reasons, one of them being that the quantity and diversity of existing contrast agents are limited. To overcome this defect, the development of new nanoparticle agents is of great interest. The properties in EPR spectroscopy of the different structures developed in the first part of this work have hence been studied and compared. The most promising system was selected and used to perform in vitro EPR imaging studies to assess their potential as EPRI contrast agent.