Vectorisation de petits acides nucléiques par des lipopolyplexes : application au cancer du sein

Abstract : During this thesis, I used complexes made with nucleic acids, cationic polymer and cationic liposomes called Lipopolyplexes to formulate siRNA (LPRi) and DNA molecular decoy (LPD) in order to inhibit the growth of 4T1 cells, a murine model of mammary carcinoma. In a first study, systemic or endotracheal injections of LPRi comprising anti-luciferase siRNA did not allow luciferase inhibition in pulmonary metastases induced by 4T1-Luc cells. From these results, LPRi were improved by targeting 4T1 cells using incorporation, by different means, of uPA and/or RGDc peptide or folic acid in liposomes. Resulted formulations were characterized, their internalization and siRNA transfection efficiency were measured in vitro. This second part showed that folate targeting of LPRi was the best formulation. In a third part, proliferation inhibition of 4T1 cells was investigated by targeting the STAT3 transcription factor. Anti-STAT3 siRNA LPRi showed very good efficacy in inhibiting STAT3, but without significant antiproliferative effect. Anti-STAT3 decoy LPD showed a very good antiproliferative effect, the latter being reinforced when co-delivery siRNA/DNA decoy (LPRiD) was performed. In vivo, a growth retardation of 4T1 tumors was observed after co-delivery siRNA/DNA decoy. This thesis demonstrated the effectiveness of lipopolyplexes for combined delivery of siRNA and DNA decoy in the 4T1 tumor cells. Some studies are however required to increase their in vivo delivery into the tumor.
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Marie-Pierre Gosselin. Vectorisation de petits acides nucléiques par des lipopolyplexes : application au cancer du sein. Biologie cellulaire. Université d'Orléans, 2016. Français. ⟨NNT : 2016ORLE2017⟩. ⟨tel-01431075⟩

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