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Évaluation et caractérisation de l'efficacité thérapeutique de nanoparticules multifonctionnelles pour de la thérapie photodynamique interstitielle appliquée au glioblastome

Abstract : Despite heavy treatments, local recurrence of glioblastoma (GBM) remains frequent, leading to a poor prognosis with a median survival of 15 months. One of the main challenges is to eradicate the infiltrating part of the tumor tissue that causes recurrence while preserving the healthy brain parenchyma from irreversible damage. To this end, neuropilin-1 (NRP-1), a receptor overexpressed by endothelial cells of angiogenic phenotype of the tumor vasculature and associated with proliferation and migration of GBM has been demonstrated to be a relevant molecular target to promote the anti-vascular effect of photodynamic therapy (PDT). The KDKPPR peptide moiety targeting NRP-1 and a porphyrin acting as a photosensitizer (PS) have thus been grafted onto AGuIX design nanoparticles to meet these challenges. The photophysical properties of the PS and the molecular affinity of the KDKPPR peptide for the NRP-1 recombinant protein were preserved after the functionalization of the AGuIX nanoparticle. In vivo selectivity studies revealed prolonged retention of peptide-conjugated nanoparticles in the vascular system of xenografted human GBMs. Post-PDT follow-ups have shown promising responses associating delayed tumor growth and a reduction in tumor metabolism in the days following treatment. We also demonstrated an acute inflammation and the formation of edema within and around the tumor in the days following the treatment as well as an influx of macrophages in the tumor which in these conditions could largely participate in the inflammatory and post-PDT immunogen response. Finally, by using a monocytic cell line (THP-1) brought into contact with the conditioned medium from tumor cells treated with PDT, we were able to demonstrate the immunostimulatory effects of PDT and in particular its potential to induce the polarization of macrophages towards the inflammatory and anti-tumor phenotype M1.
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https://hal.univ-lorraine.fr/tel-03451476
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Submitted on : Friday, November 26, 2021 - 2:44:43 PM
Last modification on : Monday, November 29, 2021 - 3:13:59 AM

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  • HAL Id : tel-03451476, version 1

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Mickaël Gries. Évaluation et caractérisation de l'efficacité thérapeutique de nanoparticules multifonctionnelles pour de la thérapie photodynamique interstitielle appliquée au glioblastome. Cancer. Université de Lorraine, 2021. Français. ⟨NNT : 2021LORR0158⟩. ⟨tel-03451476⟩

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