Thesis presented September 30, 2022

Abstract:
Radiotherapy is the most commonly used treatment for cancer. It can induce the death of cancer cells by creating DNA damage. This damage can be the result of direct ionization or indirect ionization through the formation of reactive oxygen species. One of the limitations of radiotherapy is the tolerance of healthy tissues surrounding the tumor to ionizing radiation. The dose required to sterilize the tumor is often higher than the tolerance of the surrounding healthy tissues. To overcome this problem and thus improve the effectiveness of radiotherapy, one solution could be to induce a differential effect between the tumor and the healthy tissues by loading the tumor with nanoscintillators before irradiation.
Nanoscintillators are nanoparticles usually composed of elements of high atomic number that convert ionizing radiation into photons that can span an energy range from ultraviolet (UV) to infrared, thus becoming local sources of light. The emission wavelength of these nanoscintillators depends on their composition. When we combine radiotherapy with the use of nanoscintillators, several effects are expected:
- The conventional radiotherapeutic effect induced by the X-rays.
- A radiation dose-enhancement induced by the elements of high atomic number of which nanoscintillators are composed.
- An effect due to UV photons that can be directly emitted by the nanoscintillators.

My thesis project consists in studying the capacity of nanoscintillators to improve radiotherapy and to determine the different effects involved. To carry out my project, I tested lutetium in the form of LuCl₃ salts and LuPO₄:Pr³⁺ UV emitting nanoscintillators.
Regarding the increase of the radiation dose, irradiation in the presence of nanoparticles made of heavy atoms generates an overproduction of photoelectrons and Auger electrons which in turn induce an increase of the deposited dose. We studied this effect using three different approaches:
- Physical: we were able to measure the dose-enhancement factor using the dosimetric NIPAM gels which are usually used to validate the spatial distribution of the dose during treatment. These gels are usually analyzed by MRI, but we also validated the use of an easier and more accessible technique, the optical scanner.
- Biological: we studied the efficacy of a treatment combining nanoscintillators and irradiation on a F98 murine glioma cell line using different tests. Nanoscintillators were internalized and accumulated in cytoplasmic vesicles. Incubation of cells with nanoscintillators 24 hours before irradiation induced an increase in cell death and an increase in DNA breaks formed.
- Analytical: the hydroxyl radicals formed by irradiation are very reactive with biological molecules and in particular with nucleic bases, which induces the formation of oxidative lesions. The increase of the deposited dose induces an increase of the formation of hydroxyl radicals HO° and thus of the oxidative lesions formed. These lesions can be measured by a very sensitive and specific analytical method which is the "Ultra Performance Liquid Chromatography" coupled with tandem mass spectrometry.
As for the UV effect, UV radiation is a radiation with a wavelength lower than visible light and higher than X-rays. Its effect is related to the direct absorption of UV photons by DNA bases. Therefore, it is known to have particularly toxic effects, including producing specific DNA damage that are pyrimidine dimers.
All these methods have been used to evaluate the effectiveness of loading the tumor with nanoscintillators prior to irradiation.

Keywords:
Nanoparticles, Cancer, Synchrotron x-rays, Radiotherapy