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Conception, Synthèse et Caractérisation de Nouveaux Systèmes de Guidage et de Vectorisation pour la Cancérologie

Abstract : Proliferating endothelial cells, but not quiescent endothelial cells, over-express the alphaV beta3 integrin (aVb3). This receptor has thus become an attractive target to reach tumour neo-angiogenesis and to prevent tumour progression and metastasis. For this purposes, we designed and studied a new bi-functional synthetic vector named RAFT(c[-RGDfK-])4. The core of the vector is composed of a cyclic decapeptide scaffold (RAFT) presenting two distinct domains. These allow the spatial separation of both functions of the vector and prevent the molecules from the lower face to interfere with the targeting functions. Multivalent presentation of cyclo[-RGDfK-] peptides provides the targeting duty and ensure multivalent interactions of the vector with the target receptors. Convergent synthesis of RAFT(c[-RGDfK-])4 was achieved through efficient chemoselective oxime ligations. Conjugation of the vector with diverse detection molecules (biotin, fluorescein, cyanin 5) allowed its biological evaluation in vitro and in vivo. RAFT(c[-RGDfK-])4 proved to induce aVb3 integrin clustering on HEK293(b3) cells. Its cellular uptake was shown to occur through a receptor-mediated endocytosis. When administered systemically to immuno-deficient mice, (Cy5)RAFT(c[-RGDfK-])4 detected solid tumours as well as disseminated metastasis. In order to increase its therapeutic efficacy, we conjugated RAFT(c[-RGDfK-])4 to various cytotoxic drugs. (KLAKLAK)2 peptide, doxorubicin and A chain of ricin were linked through disulfide bridge allowing their release into the target cells.
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Contributor : Elisabeth Garanger Connect in order to contact the contributor
Submitted on : Tuesday, July 26, 2005 - 2:28:34 PM
Last modification on : Monday, July 12, 2021 - 3:04:01 PM
Long-term archiving on: : Friday, April 2, 2010 - 10:19:04 PM


  • HAL Id : tel-00009834, version 1




Elisabeth Garanger. Conception, Synthèse et Caractérisation de Nouveaux Systèmes de Guidage et de Vectorisation pour la Cancérologie. Autre. Université Joseph-Fourier - Grenoble I, 2005. Français. ⟨tel-00009834⟩



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