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Thérapie photodynamique ciblant la vascularisation tumorale par l'adressage du co-récepteur neuropiline-1 :vers l'élaboration de peptides biologiquement plus stables

Abstract : Photodynamic therapy (PDT) is a treatment modality against small localized tumors, based on the combined action of a photosensitizer (PS), light and oxygen. A new method of PDT, the VTP (vascular targeted photodynamic therapy) was studied. The purpose of our strategy is to promote the anti-vascular effect of PDT by targeting the tumor vasculature. We studied the behaviour of the tetraphenylchlorine (TPC) conjugated, via the Ahx spacer, to a VEGF co-receptor (neuropilin-1) specific heptapeptide (ATWLPPR), in vitro and in vivo. A comparative study of TPC versus the conjugated PS, TPC-Ahx-ATWLPPR, allowed us to identify in vitro, using a technique of RNA interference-mediated silencing of NRP-1, a receptordependent uptake of the conjugate. In vivo, a preferential accumulation of TPC-Ahx-ATWLPPR in endothelial cells and its anti-vascular effect were demonstrated. A study of stability in vitro and in vivo of the conjugate was conducted. In vivo, the peptide sequence was degraded 4 h after intra-venous injection. Pharmacokinetics and tissue biodistribution studies of TPC-Ahx ATWLPPR and its main degradation product, TPC-Ahx-A, was performed in bearing nude mice. The degradation process of the peptide is important in the organs of the reticuloendothelial system, where the accumulation of the conjugate is majority. In order to improve in vivo stability of the targeting-peptide, new peptides were design and tested. The pseudopeptide Aψ[CH2NH] TWLPPR bound NRP-1, and after coupling with the PS, no degradation is observed in plasma in vivo 4 h after intra-venous injection.
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https://tel.archives-ouvertes.fr/tel-00389034
Contributor : Didier Maquin <>
Submitted on : Thursday, May 28, 2009 - 9:04:52 AM
Last modification on : Friday, October 23, 2020 - 8:38:04 AM
Long-term archiving on: : Monday, October 15, 2012 - 11:15:43 AM

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Noémie Thomas. Thérapie photodynamique ciblant la vascularisation tumorale par l'adressage du co-récepteur neuropiline-1 :vers l'élaboration de peptides biologiquement plus stables. Biologie cellulaire. Université Henri Poincaré - Nancy I, 2009. Français. ⟨tel-00389034⟩

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