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Edifices théranostiques pour l’ingénierie en bioimagerie IRM et photothérapie dynamique in vitro et in vivo préclinique contre le cancer

Abstract : The development of new therapeutic strategies to fight cancer is essential today. Indeed, some chemotherapies induce very important side effects and some treatments imply a bad prognosis. Alternative therapies are therefore necessary. This project aims to develop new molecular theranostic agents designed for magnetic resonance imaging (MRI) and photodynamic therapy (PDT) in vivo. The objective is to optimize a treatment by showing that it is possible to treat and monitor by bioimaging the effects of the treatment in vivo in preclinical studies. These theranostic agents associated with PDT are of considerable clinical interest as they are likely to achieve a localized treatment that can be activated temporally, with an optimized dosage, minimally invasive and with limited side effects. We will focus on the case of colon cancer in a mouse model, the third most common cancer. Therefore, we have evaluated the in vitro and in vivo efficacy of a first PS-Gd1 agent already synthesized. We then developed a new bifunctional molecular compound PS-Gd2 containing four macrocyclic gadolinium DOTA (III) complexes functionalized to a porphyrin derivative. The r1 and r2 relaxivities measured at 7T of both molecules showed a clear increase compared to the corresponding commercial contrast agents. They also show a good quantum yield of singlet oxygen. On healthy and tumor cells (murine tumor CT26) the cytotoxicity is low while the phototoxicity is remarkable on tumor cells in particular. In vivo biodistribution studies were performed on Balb-C mice after an IV injection of 100 μL of molecule at 10 mM Gd and a follow-up for 48h by MRI (Bruker, 7T) with a dynamic contrast-enhanced acquisition of the developed DCE type where we observed the accumulation of our molecules preferentially in tumors for about 6 hours. The application and evaluation of the PDT treatment in vivo on mice with CT26 colon tumors showed the efficacy of our molecules with an increase in the rate of necrosis, the appearance of vascular damage as well as inflammation and an immune response leading to an absence of tumor volume growth.
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Submitted on : Friday, July 15, 2022 - 10:28:14 AM
Last modification on : Saturday, July 16, 2022 - 3:47:56 AM

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Sarah Boumati. Edifices théranostiques pour l’ingénierie en bioimagerie IRM et photothérapie dynamique in vitro et in vivo préclinique contre le cancer. Chimie thérapeutique. Université Paris sciences et lettres, 2021. Français. ⟨NNT : 2021UPSLC006⟩. ⟨tel-03723713⟩

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