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Conception, synthèse et activité biologique de vecteurs peptidiques pour le ciblage et/ou la thérapie du cancer

Abstract : This thesis work is about conception, synthesis and biological activities of peptide vectors for diagnostic and/or therapeutic applications against cancer.We used cyclodecapeptidic scaffolds chemoselectively handled with targeting elements and effectors. Those scaffolds presenting four c[RGDfK] ligands have a strong affinity for integrin avB3 receptors, wich are overexpressed in various cancers and by endothelial cells from the tumor surrounding. They are poorly expressed in healthy tissues. The multivalent presentation of -RGD- motifs higly increases the internalisation of the scaffold by tumor cells. Thus we developed molecules composed by four -RGD- motifs for tumor targeting, and different effectors for various applications. Thanks to multiple collaborations, we linked the vector to a highly cytotoxic compound (cryptophycine), a photosensitiser (DHP), a pro-apoptotic peptide (BAX), a DOTA complex (for 68-Ga complexation, for PET applications). We also grafted the cyclodecapeptide bearing four -RGD- motifs to polymers or silica nanoparticles, both fluorescent.The main project of this thesis was the conception of dual targeting vectors. Our objective was to simultaneously target two receptors overexpressed in the tumor periphery. Beside the targeting of avB3, we decided to target the NRP1 receptor, which is also overexpressed during tumor angiogenesis. We exploited various chemoselective reactions (oxime, huisgen cycloaddition, peptide coupling) to synthesise fluorescent vectors targeting one of the two receptors, or both. In vitro and in vivo biological experiments were realised. We discovered that dual targeting compounds allow a really good tumor detection, but inferior to mono targeting ones. Nevertheless, the cellular answer triggered by dual targeting compounds is totally different from those obtained with other compounds, including co-injection. We found different elements that tend to show that a NRP1-vector-integrin could be formed, and would be blocked inside the cellular membrane, resulting in its internalisation's blocking.
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Submitted on : Wednesday, January 17, 2018 - 10:45:06 AM
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Fabien Thoreau. Conception, synthèse et activité biologique de vecteurs peptidiques pour le ciblage et/ou la thérapie du cancer. Biochimie, Biologie Moléculaire. Université Grenoble Alpes, 2017. Français. ⟨NNT : 2017GREAV006⟩. ⟨tel-01686229⟩