Yes / Despite considerable progress with our understanding of glioblastoma multiforme (GBM) and the precise delivery of radiotherapy, the prognosis for GBM patients is still unfavorable with tumor recurrence due to radioresistance being a major concern. We recently developed a cross-linked iron oxide nanoparticle conjugated to azademethylcolchicine (CLIO-ICT) to target and eradicate a subpopulation of quiescent cells, glioblastoma initiating cells (GICs), which could be a reason for radioresistance and tumor relapse. The purpose of our study was to investigate if CLIO-ICT has an additive therapeutic effect to enhance the response of GBMs to ionizing radiation. Methods: NSG™ mice bearing human GBMs and C57BL/6J mice bearing murine GBMs received CLIO-ICT, radiation, or combination treatment. The mice underwent pre- and post-treatment magnetic resonance imaging (MRI) scans, bioluminescence imaging (BLI), and histological analysis. Tumor nanoparticle enhancement, tumor flux, microvessel density, GIC, and apoptosis markers were compared between different groups using a one-way ANOVA and two-tailed Mann-Whitney test. Additional NSG™ mice underwent survival analyses with Kaplan–Meier curves and a log rank (Mantel–Cox) test. Results: At 2 weeks post-treatment, BLI and MRI scans revealed significant reduction in tumor size for CLIO-ICT plus radiation treated tumors compared to monotherapy or vehicle-treated tumors. Combining CLIO-ICT with radiation therapy significantly decreased microvessel density, decreased GICs, increased caspase-3 expression, and prolonged the survival of GBM-bearing mice. CLIO-ICT delivery to GBM could be monitored with MRI. and was not significantly different before and after radiation. There was no significant caspase-3 expression in normal brain at therapeutic doses of CLIO-ICT administered. Conclusion: Our data shows additive anti-tumor effects of CLIO-ICT nanoparticles in combination with radiotherapy. The combination therapy proposed here could potentially be a clinically translatable strategy for treating GBMs.

Le cancer est une des premières causes de mortalité dans le monde. Avec la chirurgie, la radiothérapie est une des thérapies curatrices essentielles en cancérologie. Elle consiste à utiliser les propriétés des rayonnements ionisants pour induire la mort des cellules cancéreuses. Néanmoins, du fait de la radiorésistance d’un certain nombre de tumeurs, nécessitant des doses délivrées intolérables pour les tissus sains environnants, de nombreux développements sont en cours pour limiter la dose délivrée et augmenter la radiosensibilité des tumeurs actuellement radio-résistantes. Parmi les stratégies envisagées, l’utilisation de nanoparticules théranostiques inorganiques ouvre des perspectives très intéressantes car il deviendrait possible de faire parvenir en quantité suffisante ces nanoparticules dans une tumeur après injection intraveineuse. Au sein du Laboratoire de Physico-Chimie des Matériaux Luminescents, les physico-chimistes ont développé des nanoparticules inorganiques d’un diamètre inférieur à 5 nm, permettant leur injection intraveineuse et leur élimination urinaire. Notre travail de thèse a porté sur la validation préclinique de deux types de nanoparticules (1- à coeur d’oxyde de gadolinium ; 2- nanoparticules d’or) en tant qu’agents radiosensibilisants permettant d’augmenter l’effet de la radiothérapie externe par rayons X sur divers types de tumeurs radio-résistantes : le gliosarcome, le carcinome épidermoïde du larynx et l’ostéosarcome. Les résultats obtenus aussi bien pour les nanoparticules d’oxyde de gadolinium que pour les nanoparticules d’or sont très prometteurs et laissent entrevoir un potentiel d’application en tant qu’agents de thérapie guidée par l’imagerie. / Cancer is a leading cause of death worldwide. With surgery, radiation therapy is an essential to cure tumors. Radiotherapy consists in using the properties of ionizing radiations to induce cancer cell death. However, because of the radioresistance of some tumors, requiring unacceptable dose delivered to surrounding healthy tissue, many developments are underway to limit the dose and increase the radiosensitivity of radio-resistant tumors. Among the proposed strategies, the use of inorganic theranostic nanoparticles opens very interesting perspectives since it should be possible to target sufficient nanoparticles into the tumor of interest following an intravenous injection. In the Laboratoire de Physico-Chimie des Matériaux Luminescents, chemists have developed inorganic nanoparticles with diameters below 5 nm, allowing their intravenous injection and urinary excretion. Our thesis has focused on the preclinical validation of two types of nanoparticles (1- based on gadolinium oxide, 2- based on gold) as radiosensitizing agents to increase the effect of external beam X-ray radiation on various types of radioresistant tumors : gliosarcoma, squamous cell carcinoma of the larynx and osteosarcoma. The results for both gadolinium oxide nanoparticles and gold nanoparticles are very promising and open the way for potential applications for imaging-guided therapy.