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Développement de nouvelles plateformes pour l’amélioration du traitement du glioblastome par thérapie photodynamique

Abstract : The treatment of malignant brain tumors, of which glioblastoma multiform is the most aggressive form, is a major challenge in oncology. Photodynamic therapy (PDT) appears to be a promising technique in this context. PDT destroys cancer cells by the action of three elements: a photosensitizer (PS), light and oxygen. After photoexcitation under visible light, PS generates, in the presence of oxygen, the formation of reactive oxygen species including singlet oxygen (1O2), toxic, which will destroy surrounding tissues. Unfortunately, PDT suffers from two major drawbacks which are the lack of selectivity of many PSs currently used clinically as well as the need for oxygen to be effective. To overcome the lack of selectivity, targeting tumor neovessels is a promising approach. The affinity of KDKPPR peptide for the overexpressed NRP–1 receptor on endothelial cells has already been demonstrated by our team. Regarding the lack of oxygen, we were interested in alkoxyamines able of generating toxic alkyl radicals by light activation, even in hypoxic environment. These photoactivatable alkoxyamines are described in the literature but never used in tumor treatment. In this thesis, we developed a trimodal platform combining a PS and a photoactivatable alkoxyamine for PDT in normoxic and hypoxic medium, respectively, and a peptide to target NRP–1. The synthesis of this platform was successfully performed. The platform study confirmed the conservation of the ability to form 1O2 and the NRP–1 affinity. The detection of the photogenerated radicals from alkoxyamine is detected by EPR spectroscopy. Although promising, this platform is not applicable in PDT due to the use of an unsuitable UV wavelength for photoactivation of alkoxyamine. The second part of this thesis was devoted to the platform optimization. We focused on three avenues: 1) Design of a new alkoxyamine absorbing at higher wavelengths, 2) Improvement of the platform solubility by grafting a cyclodextrin and 3) Development of a new NRP–1–targeted peptide which can be internalized in cells.
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Submitted on : Wednesday, September 8, 2021 - 3:22:34 PM
Last modification on : Thursday, September 9, 2021 - 3:27:05 AM

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Ludivine Larue. Développement de nouvelles plateformes pour l’amélioration du traitement du glioblastome par thérapie photodynamique. Génie des procédés. Université de Lorraine, 2021. Français. ⟨NNT : 2021LORR0045⟩. ⟨tel-03338347⟩

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