Monte Carlo microdosimetry of charged-particle microbeam irradiations

The interaction of charged-particles with matter leads to a localized energy deposits in sub-micrometric tracks. This unique property makes this type of ionizing radiation particularly interesting for deciphering the radiation-induced molecular mechanisms at the cell scale. Charged-particle microbeams (CPMs) provide the ability to target a given cell compartment at the micrometer scale with a controlled dose down to single particle. My work focused on irradiations carried out with the CPM at the AIFIRA facility in the CENBG (Applications Interdisciplinaires des Faisceaux d'Ions en Region Aquitaine). This microbeam delivers protons and α-particles and is dedicated to targeted irradiation in vitro (human cells) and in vivo (C. elegans). In addition to their interest for experimental studies, the energy deposits and the interactions of charged-particles with matter can be modeled precisely along their trajectory using track structure codes based on Monte Carlo methods. These simulation tools allow a precise characterization of the micro-dosimetry of the irradiations from the detailed description of the physical interactions at the nanoscale to the prediction of the number of DNA damage, their complexity and their distribution in space. During my thesis, I developed micro-dosimetric models based on the Geant4-DNA modeling toolkit in two cases. The first concerns the simulation of the energy distribution deposited in a cell nucleus and the calculation of the number of different types of DNA damage (single and double strand breaks) at the nanometric and micrometric scales, for different types and numbers of delivered particles. These simulations are compared with experimental measurements of the kinetics of GFP-labeled (Green Fluorescent Protein) DNA repair proteins in human cells. The second is the dosimetry of irradiation of a multicellular organism to study the genetic instability in a living organism during development (C. elegans). I simulated the distribution of the energy deposited in different compartments of a realistic 3D model of a C. elegans embryo following proton irradiations. Finally, and in parallel with these two studies, I developed a protocol to characterize the AIFIRA microbeam using fluorescent nuclear track detector (FNTD) for proton and α-particle irradiations. This type of detector makes it possible to visualize in 3D the incident particle tracks with a resolution of about 200 nm and to examine the quality of the cellular irradiations carried out by the CPM. (author)