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Ciblage de la neuropiline-1, co-récepteur du VEGF, pour potentialiser l'effet anti-vasculaire de la thérapie photodynamique

Abstract : Tumor growth beyond a few mm3 requires the formation of its own vascular network by angiogenesis ; the destruction of these vessels could lead to tumor regression. Angiogenesis is controlled by numerous growth factors, including VEGF (Vascular Endothelial Growth Factor). Photodynamic therapy (POT) can be used as an anti-cancer treatment, and is based on the combined action of a photosensitizer (PS), light and oxygen. Tumor destruction results not only from direct damage to tumor cells, but also from indirect damage to the tumor vasculature and immunological effects. A new PS conjugated to an heptapeptide (ATWLPPR) targeting neuropilin-1, a VEGF coreceptor, has been synthesized. This coupling did not change the photophysical properties of the PS. An in vitro study on human umbilical vein endothelial celIs showed a lower dark cytotoxicity, improved intracellular uptake and photodynamic activity, for the conjugated PS, compared to the non-conjugated PS, due to coupling to the peptide. ln vivo, in human malignant glioma-bearing nude mice, the conjugated PS is incorporated in the tumor at higher levels than in the skin. With POT conditions (PS dose, light fluence and fluence rate) that have been optimized using an experimental design approach, POT with the conjugated PS induces blood flow reduction during treatment, compared to the non-conjugated PS, a destruction of blood vessels endothelial celIs, 24h post-POT, and a statistically significant tumor growth delay, compared to the non-conjugated PS. An in vitro and in vivo study revealed a good stability of the peptidic moiety of the molecule up to 4h after intravenous injection in vivo, but the use of peptidases-resistant pseudo-peptides would increase further its efficacy.
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Submitted on : Thursday, March 29, 2018 - 10:49:25 AM
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  • HAL Id : tel-01747009, version 1



Loraine Tirand. Ciblage de la neuropiline-1, co-récepteur du VEGF, pour potentialiser l'effet anti-vasculaire de la thérapie photodynamique. Biotechnologies. Université Henri Poincaré - Nancy 1, 2007. Français. ⟨NNT : 2007NAN10162⟩. ⟨tel-01747009⟩



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