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Theoretical Modeling from Functionalized Gold Nanoparticles to Repair of Lesions in DNA for cancer radiotherapy

Abstract : The potential of gold nanoparticles (AuNPs) to improve the performance of radiotherapy is demonstrated by numerous in vivo and in vitro experimental studies. These metallic particles increase significantly the radiosensitization effect. Upon water radiolysis, AuNPs generate reactive oxygen species that amplify DNA damage and lead to a greater destruction of cancerous cells. Nevertheless, for a more optimal therapeutic efficacy, several properties of AuNPs must be taken into account during the synthesis, such as their size, shape and surface which can tune their catalytic effects in the biological environment (mainly liquid water). These structural aspects are not yet examined in the state-of-the-art, either experimentally or theoretically. This thesis aims to rationalize the stability of AuNPs in the presence of chemical or biological environment before irradiation by using theoretical approaches. Firstly, we have modeled the stability of AuNPs in the range 1- 3.4 nm. We have then studied the behavior of these nanoparticles in a biological (hydration) and chemical (PEGylation) model environment, and the combination of the two environments. When 0.9-1.8 nm nanoclusters interact with a complete shell of water molecules, we have shown that metastable ino-decahedrons (in vacuum) are transformed into more favourable metastable icosahedrons. While in the presence of monoshell of PEG ligands, the strong Au-S bond and the hydrogen bonds between the ligands induce a significant deformation on the nanoparticle morphology, i.e. stellation of the Au54 decahedron. In addition, we have shown that PEG ligands promote the confinement of a few water molecules in the vicinity of AuNPs. Our conclusions open interesting perspectives for the theoretical modeling of water radiolysis. In parallel with these studies, we have focused on the characterization of different types of DNA lesions. Two projects have been performed: firstly, we have studied the interaction of a trilysine peptide with an oligonucleotide which could lead to the formation of DNA-polyamine cross link. Then, the second project focuses on rationalizing different repair rates of cyclobutane pyrimidine dimers in the presence of the DDB2 recognition enzyme at the atomic scale.
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Chen Hui Chan. Theoretical Modeling from Functionalized Gold Nanoparticles to Repair of Lesions in DNA for cancer radiotherapy. Theoretical and/or physical chemistry. Université de Lyon, 2019. English. ⟨NNT : 2019LYSEN020⟩. ⟨tel-02472084v2⟩

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