Targeting of neuropilin-1 to improve the anti-vascular effect of photodynamic therapy in xenograft human malignant glioma - Archive ouverte HAL Accéder directement au contenu
Communication Dans Un Congrès Année : 2008

Targeting of neuropilin-1 to improve the anti-vascular effect of photodynamic therapy in xenograft human malignant glioma

Résumé

The principle of photodynamic therapy (PDT) is based on the combined action of a photosensitizer (PS) localized in the tumor, light and oxygen. After light irradiation of the PS and in the presence of molecular oxygen, photo-oxydation reactions will lead to the production of reactive oxygen species, inducing a localized eradication of the tumor. However, PDT effects are mediated not only through direct killing of tumor cells but also through indirect effects, involving both initiation of an immune response and destruction of the neovasculature (anti-vascular effect). The strategy developed in the laboratory aims to favour this anti-vascular effect by targeting tumor neovasculature. This approach was considered by coupling a PS (chlorin) to the heptapeptide ATWLPPR, targeting neuropilin- 1 (NRP-1), a VEGF165 (Vascular Endothelial Growth Factor, isoform 165) co-receptor. We previously confirmed molecular and cellular affinity for the conjugated PS and its in vitro photocytotoxicity (Tirand et al., J. Control Release, 2006). In vivo, we demonstrated that only the conjugated PS allowed a selective accumulation in endothelial cells lining tumor vessels (Thomas et al., Photochem. Photobiol. Sci., 2008). Metabolic profile and optimization of treatment conditions were performed in nude mice xenografted ectopically with U87 human malignant glioma cells (Tirand et al., Drug Metab. Dispos., 2007). The aim of this study was to validate and to characterize in vivo the anti-vascular approach after PDT using the conjugated PS, compared to the non-conjugated PS. The anti-vascular effect, for the conjugated PS, was characterized by a reduction in blood flow around 50% during treatment, a loss of the CD31 labelling integrity in endothelial cells from two hours post-PDT. In fine, 4 hours post-PDT, we observed for the conjugated-PS, microhemorrhages, vascular stasis and lumen trombosis confirmed by a decrease of the fibrinogen diffusion in tumor tissue. Following PDT, for this PS, endothelial cells became rounded but without change of morphological characteristics of the ultrastructures. In vivo, the photodynamic efficiency with the conjugated PS induced a statistically significant tumor growth delay compared to the non-coupled PS. This targeting strategy of NRP-1 using a heptapeptide displays the potential of anti-vascular effect of PDT for glioblastomas treatment.

Domaines

Biophysique

Dates et versions

hal-00323582 , version 1 (22-09-2008)

Identifiants

Citer

Denise Bechet, Loraine Tirand, François Plénat, Noémie Thomas, Thierry Bastogne, et al.. Targeting of neuropilin-1 to improve the anti-vascular effect of photodynamic therapy in xenograft human malignant glioma. 20th Meeting of the European Association for Cancer Research, EACR'20, Jul 2008, Lyon, France. pp.25-26, ⟨10.1016/S1359-6349(08)71274-6⟩. ⟨hal-00323582⟩
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