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 receptor-dependent 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 reticulo-endothelial 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 A[psi] [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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Noémie Thomas. Thérapie photodynamique ciblant la vascularisation tumorale par l'adressage du co-récepteur neuropiline-1 : Vers l'élaboration de peptides biologiquement plus stables. Médecine humaine et pathologie. Université Henri Poincaré - Nancy 1, 2009. Français. ⟨NNT : 2009NAN10019⟩. ⟨tel-01748489⟩

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