New generations of metallic nanoparticles to enhance the response to radiotherapy of radioresistant and invasive cancer

The use of nanoparticles containing a metal with a high atomic number is a promising approach to amplify the effects of radiotherapy, a treatment currently used in over 50% of cancer patients. Among them, AGuIX^R, a nanoparticle with theranostic properties, is currently evaluated in multiple clinical trials. This thesis work is part of the development of a second generation of AGuIX^R nanoparticles to increase their efficiency and to target metastasis formation. In a first part of this work, the gadolinium atoms (Z = 64) of AGuIX^R were replaced by yttrium (Z = 39) or bismuth (Z = 83) atoms to measure the impact of the atomic number on radiosensitization. Despite a lack of reproducibility of the chemical synthesis, a superior radiosensitizing effect is observed in vitro with the nanoparticles containing bismuth. The second part of this work was dedicated to the evaluation of CuPRiX nanoparticles, containing both gadolinium and free chelates. They allow the in-situ chelation of copper, a trace element involved in the growth and migration mechanisms of tumor cells. Firstly, in vitro studies on three cell models of oral, breast and lung cancers showed that CuPRiX was able to slow down cell migration and invasion, inhibit the activity of the copper-dependent enzyme Lysyl Oxidase (LOX) involved in these processes, and radiosensitize tumor cells. Secondly, the efficacy of CuPRiX was validated in vivo in a mouse model of metastatic breast cancer. This study showed a strong reduction in tumor growth and the number of metastases thanks to copper chelation, while maintaining a good radiosensitizing effect. This new generation of nanoparticles combining radiosensitization and copper chelation appears to be a promising strategy in the treatment of radioresistant and metastatic cancers. (author)