Applications of Noble Metal Nanoclusters for Diagnostic andTargeting Cancer Therapy ; Applications des nanoclusters de métaux nobles pour lediagnostic et la thérapie ciblée du cancer

Gold nanoparticles (Au NPs) have shown promising results in nanomedicine applied to oncology. They are capable of accumulating in tumor areas, inducing a therapeutic effect by delivering drugs or a photo-/radiotherapeutic effect thanks to their energy absorption properties. They also allow diagnosis by different imaging techniques. This dual activity defines them as theranostic agents. Gold nanoclusters (Au NCs) define an interesting sub-family of Au NPs. They are composed of about ten to hundred gold atoms stabilized by organic molecules. Their size smaller than ~8 nm allows them to be eliminated by the kidneys and to exhibit photoluminescence (PL) properties until infrared wavelengths, which are suitable for in vivo optical imaging. They can also induce cell death under irradiation due to the intrinsic properties of gold. Their optical features, pharmaco-kinetic and tumor accumulation are highly sensitive to size and surface chemistry modification. Currently, preclinical results are not sufficient for clinical transfer and it is necessary to improve the characterization of Au NCs and to study their behaviour in vitro and in vivo.In this context, my thesis project focused on the functionalization of Au NCs in order to improve their accumulation in tumors. The first strategy is based on the self-aggregation of Au NCs in the tumor microenvironment. For this purpose, the surface of the Au NCs was either functionalized with i) molecules promoting bioorthogonal click chemistry reactions, or ii) complementary oligonucleotides that can hybridize. The self-aggregation of Au NCs in solution confirmed the increase in PL by inter-particle energy transfer. The self-agregation of Au NCs could potentially improve the therapeutic effect, but the Au NCs still need to be characterized in vivo. The second strategy consisted in increasing the affinity of Au NCs for cells by adding controlled amounts of arginine on their surface. Indeed, arginine is known to promote electrostatic interaction with plasma membranes and cellular ...