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    Soutenance de thèse de Mme Chiara Bastiancich

    Soutenance de thèse de Mme Chiara Bastiancich

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    12 April 2018

    Titre : Lauroyl-gemcitabine lipid nanocapsule hydrogel for the local treatment of glioblastoma

    Directeur de Thèse :

    Pr Frédéric Lagarce (Université Angers, France), Pr Véronique Préat (Université Catholique de Louvain, Belgium), Dr. Fabienne Danhier (Université Catholique de Louvain, Belgium)

    Glioblastoma (GBM) is an aggressive malignant brain tumor characterized by rapid proliferation and propensity to infiltrate healthy brain tissue. Its standard of care therapy includes surgical resection, radiotherapy and chemotherapy with Temozolomide but GBM always recur even after multiple resection and treatment, mainly because of its high invasiveness and chemoresistance to alkylating drugs. Among the strategies that have been developed to find a solution to the devastating and incurable effects of GBM there is the local delivery of chemotherapeutic agents (implants, foams, hydrogels, microcarriers) and the use of nanomedicines. Indeed, a sustained release of the drug in the gap period between surgery and standard of care chemo-radiation could lead to a reduction of the formation of recurrences at the resection cavity borders. In this research, we evaluate the feasibility, efficacy and safety of Lauroyl-gemcitabine lipid nanocapsule (GemC12-LNC), an injectable nanomedicine hydrogel previously developed in our group, for the local treatment of GBM.

    GemC12-LNC is uniquely formed of lipid nanocapsules and the prodrug Lauroyl-gemcitabine and, in this study, it was optimized to obtain a sustained release of the drug over time. The GemC12-LNC hydrogel was prepared by a phase-inversion technique process and characterized. It is injectable, adapted for brain implantation and able to sustainably release the drug in vitro. The lipid nanocapsules integrity was demonstrated ex vivo during one week using fluorescent-labeled GemC12-LNC hydrogel. In healthy mice brain, no inflammation, apoptosis or microglia activation was observed after one week, two months and six months of exposure to the hydrogel suggesting that this system is well tolerated and suitable for an application in the brain. Intratumoral injection of GemC12-LNC hydrogel in a U87 subcutaneous and orthotopic GBM model significantly reduced tumor growth and increased the animal’s median survival compared to the controls, respectively. Moreover, to mimic the clinical setting, an innovative and reproducible “biopsy punch” tumor resection technique of U87 GBM was developed and the GemC12-LNC hydrogel slowed down the formation of recurrences in the brain. Successively, a second molecule was loaded in the oily core of the nanocapsules obtaining a multi-drug loaded hydrogel (e.g. GemC12 + Paclitaxel, GemC12 + Salinomycin) with similar physicochemical and injectability properties. To test this combination, the tumor resection technique was optimized for rats using the aggressive 9L orthotopic model.

    In conclusion, the feasibility efficacy and safety of GemC12-LNC have been shown in vitro and in several preclinical in vivo models showing that this nanomedicine hydrogel is a promising and innovative delivery system for the local treatment of GBM. This gel, which can be directly injected in the GBM resection cavity, has a very simple formulation, combines the properties of nanomedicines and hydrogels, is able to deliver two anti-cancer drugs simultaneously.

    This work has expanded the knowledge about the use of Gemcitabine derivatives against GBM and we hope that other groups will focus on its potential use for this tumor. The surgical procedure that has been developed in rodents to resect GBM orthotopic tumors can be useful to test any other kind of local delivery systems. Finally, this challenging and original project showed that nanomedicine hydrogels could contribute to the cure of GBM operable tumors by reducing the formation of local recurrences in the gap period between surgery and chemoradiation.