Influence of hypoxia on the internalization and radioenhancement effect of bismuth-platinum nanoparticles in tumor cells treated with photon and fast ions

External radiotherapy plays a central role in the treatment arsenal of more than half of all cancer patients. However, its use is restricted by the side-effects on healthy tissue and the radioresistance often present in tumors. It is therefore crucial to explore alternative therapeutic methods to overcome these limitations. The combination of nanoagents with external radiotherapy is proposed as a strategy to increase the effect of radiation on the tumor, with the aim of achieving the same therapeutic effect with a lower total dose delivered to the patient. As these nanoagents are detectable by medical imaging, their concentration in the tumor after injection can be determined and diagnosis improved. These agents are known as 'theranostic'. When imaging and treatment are combined, we speak of 'image-guided therapy'. The combination with heavy ion beams offers promising prospects, combining the biological efficiency of ions, superior to that of X-rays, with the nanoagents. The aim of my thesis was to quantify, in vitro, the efficacy of new bimetallic nanoparticles composed of bismuth and platinum, coated with PEG diamine. After optimizing the synthesis of these agents, I assessed their toxicity and internalization capacity in cancer cell lines. Their radio-amplifying properties were evaluated in association with different types of photonic and hadronic radiations. The effect of molecular oxygen in the environment was also studied. Results showed that these nanoparticles, about 40 nm in diameter, can be functionalized with a fluorophore, rhodamine. They are stable, with low toxicity down to a concentration of 0.25 mM, and localize in the cytoplasm of cells, either in free form or concentrated in vesicles. Experiments on a 3D cell model have shown that nanoparticles are able to migrate into the extracellular matrix. Oxygen concentration had little influence on internalization. This work has also shown that these nanoparticles amplify the effect of photonic and hadronic ionizing radiation. Under normoxic conditions, they increase the effectiveness of X-rays (200 kV) by 62% at a dose of 2 Gy in HeLa cells, corresponding to a dose reduction by a factor of 1.58 (DEF) with a cell survival rate of 10%. At a dose of 2 Gy, nanoparticles also increase the efficacy of gamma radiation from a Cesium 137 source (13%) and from carbon (24%) and helium (38%) ion beams. The concentration of oxygen in the environment has a strong influence on the radiation-amplifying effect: the effect is annihilated in anoxic conditions (0% oxygen). This effect is attributed to oxygen's role in fixing molecular damage. The various stages involved in characterizing nanoparticles and their properties are essential for the development of new agents to be combined with different irradiation modalities for clinical application. Artificial intelligence could, in the future, be a tool to help choose the best combined treatment strategy. (author)