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Relations structure-effet de nanovecteurs à base de copolymères à blocs pour la thérapie photodynamique : utilisation de modèles de membranes

Abstract : Photodynamic therapy (PDT), a therapy based on the irradiation of photosensitizing molecules to generate an oxidative stress, is already used as a treatment of some pathologies. The photosensitizers used are often highly hydrophobic molecules that aggregate in aqueous medium. Therefore, used by themselves, they require to be injected at high concentrations, leading to a risk of global photosensitization. To reduce this secondary effect and increase the effectiveness of the treatment, it is possible to encapsulate those molecules. Previous work in the IMRCP laboratory has led to the development of block copolymer-based carriers to encapsulate a photosensitizer, pheophorbide-a. This work has showed superior efficiency of some type of carriers compared to others under PDT conditions on cell culture. The aim of this project was to develop tools to better understand the mechanisms occurring when using block copolymers-based nanocarriers encapsulating pheophorbide-a and during the irradiation of the photosensitizer. The nanocarriers studied were block copolymer-based micelles made of PEO-PCL, PEO-PLA and PEO-PS. To simplify the system studied, we chose to use liposomes as membrane models to simulate the biological target. Using the fluorescence properties of pheophorbide-a, we were able to obtain the affinity constants of the photosensitizer for the micelles and the lipid vesicles, and then evaluate the transfer of pheophorbide-a from the micelles to the vesicles. Following that, we investigated the phenomena occurring during the irradiation of the photosensitizer. We were able to estimate the relative production of singlet oxygen depending on the type of micelles used. By monitoring the leakage of a fluorescent probe contained in the liposomes, allowing us to evaluate their permeability, it was possible to measure the effects of singlet oxygen production on the integrity of the liposome membrane. Complementarily, we followed the oxidation of the lipids of the liposomes during the irradiation of pheophorbide-a by mass spectrometry. These results combined together allowed us to see what were the parameters influencing the PDT efficiency of micelles encapsulating a photosensitizer. We managed to classify those with the greatest effect on the integrity of model membranes among those studied.
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Maxime Demazeau. Relations structure-effet de nanovecteurs à base de copolymères à blocs pour la thérapie photodynamique : utilisation de modèles de membranes. Biotechnologie. Université Paul Sabatier - Toulouse III, 2019. Français. ⟨NNT : 2019TOU30113⟩. ⟨tel-02880020⟩

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