Ferrocifen loaded lipid nanocapsules : physico-chemical characterization and biological evaluations on ovarian cancer ; Nanocapsules lipidiques chargées en ferrocifènes : évaluations physico-chimiques et biologiques pour application dans le traitement du cancer de l’ovaire

High grade serous epithelial ovarian cancer can be characterized according to mitochondrial metabolism. Two sub-types can be distinguished : the High OXPHOS tumour which is chemosensitive and the Low OXPHOS tumour, less sensible to carboplatin and paclitaxel. The purpose of this PhD project was to study alternatives to improve treatments for these sub-types. Firstly, six ferrocifens from the succinimide family were encapsulated in LNCs. Results obtained showed differences in terms of encapsulation efficiency, depending on ferrocifen structure. Moreover, interestingly, two of the six ferrocifens led to the formation of a gel. Secondly, ferrocifen stealth LNCs were formulated and characterized. In vivo efficacy of these formulations was tested on High and Low OXPHOS ovarian Patient-derived Xenograft models, alone or in combination to standard chemotherapy (carboplatin and paclitaxel). Results obtained showed a significant improvement of the overall response rate on Low OXPHOS model treated with one of the ferrocifen-LNCs in association with paclitaxel and carboplatin, compared to chemotherapy alone. It highlighted a promising approach to treat chemotherapy resistant ovarian cancer. To finish, a strategy to specifically target ovarian cancer was thought. A cell penetrating peptide, C-TLS, was synthesized and covalently grafted at the surface of ferrocifen-LNCs. However, internalization kinetic, followed by flow cytometry, did not show any improvement by the decoration. Nevertheless, the study will be reproduced in vivo, CTLS peptide being known for its cytotoxicity on ovarian cancer. ; Le cancer épithélial de l’ovaire séreux de haut grade peut être caractérisé selon le métabolisme mitochondrial. Deux sous-types sont à distinguer : les tumeurs «High OXPHOS» qui sont chimiosensibles et les tumeurs «Low OXPHOS» moins sensibles au carboplatine et paclitaxel. Le but de cette thèse était d’étudier de nouvelles alternatives thérapeutiques pour traiter ces sous types. Tout d’abord, 6 ferrocifènes ont été encapsulés dans ...