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Conception et évaluation d'un vecteur ciblé de thérapie génique anticancéreuse destiné à la voie intraveineuse

Abstract : Intravenous administration of therapeutic DNA faces many obstacles related to its degradability and its difficulty to penetrate into the cells due to its large size and its hydrophilicity. Lipoplexes conjugated with high molecular weight hyaluronic acid (HA) have been designed in order to deliver plasmid DNA inside cancer cells expressing the membrane receptor CD44, a key receptor in the development of tumors. The use of HA conjugated to the phospholipid DOPE (HA-DOPE) and of the GFP model plasmid lead to obtain lipoplexes around 250 nm, negatively charged, which efficiently protect the DNA against nucleases and slightly stimulate the C3 fraction of the complement system. In a cellular model expressing CD44, the optimal transfection was obtained by using lipids containing 10% of HA-DOPE complexed to DNA at a 2:1 ratio. Internalization of these lipoplexes is mediated by the caveolae pathway and involves the CD44 receptor. This formulation was applied to the delivery of a therapeutic gene encoding the estrogen receptor β (ERβ), which is a potential tumor suppressor. On an in vivo xenograft model of estrogen-dependent breast cancer cells expressing CD44, decrease of the tumor volume, as well as decrease of the Ki67 proliferation index, have shown the anticancer activity of the lipoplexes conjugated to HA following intravenous administration.
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Amélie Dufay Dufaÿ. Conception et évaluation d'un vecteur ciblé de thérapie génique anticancéreuse destiné à la voie intraveineuse. Médecine humaine et pathologie. Université Paris Sud - Paris XI, 2012. Français. ⟨NNT : 2012PA114818⟩. ⟨tel-00737496⟩

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