Rapamycin-Loaded Lipid Nanocapsules Induce Selective Inhibition of the mTORC1-Signaling Pathway in Glioblastoma Cells
In: ISSN: 2296-4185 ; Frontiers in Bioengineering and Biotechnology ; https://inserm.hal.science/inserm-03374695 ; Frontiers in Bioengineering and Biotechnology, 2021, 2021
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International audience ; Inhibition of the PI3K/Akt/mTOR signaling pathway represents a potential issue for the treatment of cancer, including glioblastoma. As such, rapamycin that inhibits the mechanistic target of rapamycin (mTOR), the downstream effector of this signaling pathway, is of great interest. However, clinical development of rapamycin has floundered due to the lack of a suitable formulation of delivery systems. In the present study, a novel method for the formulation of safe rapamycin nanocarriers is investigated. A phase inversion process was adapted to prepare lipid nanocapsules (LNCs) loaded with the lipophilic and temperature sensitive rapamycin. Rapamycin-loaded LNCs (LNC-rapa) are ∼110 nm in diameter with a low polydispersity index (<0.05) and the zeta potential of about −5 mV. The encapsulation efficiency, determined by spectrophotometry conjugated with filtration/exclusion, was found to be about 69%, which represents 0.6 wt% of loading capacity. Western blot analysis showed that LNC-rapa do not act synergistically with X-ray beam radiation in U87MG glioblastoma model in vitro. Nevertheless, it demonstrated the selective inhibition of the phosphorylation of mTORC1 signaling pathway on Ser2448 at a concentration of 1 µM rapamycin in serum-free medium. Interestingly, cells cultivated in normoxia (21% O 2) seem to be more sensitive to mTOR inhibition by rapamycin than those cultivated in hypoxia (0.4% O 2). Finally, we also established that mTOR phosphorylation inhibition by LNC-rapa induced a negative feedback through the activation of Akt phosphorylation. This phenomenon was more noticeable after stabilization of HIF-1α in hypoxia.
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Rapamycin-Loaded Lipid Nanocapsules Induce Selective Inhibition of the mTORC1-Signaling Pathway in Glioblastoma Cells
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Autor/in / Beteiligte Person: | Séhédic, Delphine ; Roncali, Loris ; Djoudi, Amel ; Buchtova, Nela ; Avril, Sylvie ; Chérel, Michel ; Boury, Frank ; Lacoeuille, Franck ; Hindré, François ; Garcion, Emmanuel ; Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17) ; Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA) ; Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE) ; Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE) ; Université de Nantes (UN)-Université de Nantes (UN) ; Nuclear Oncology (CRCINA-ÉQUIPE 13) ; EUROPE : EURONANOMED III 2019-075 (GLIOSILK : Silk-fibroin interventional nano-trap for the treatment of glioblastoma) ; Région Pays-de-la-Loire & Cancéropole Grand-Ouest : NanoFar+ program (International strategy) funded by La Région Pays-de-la-Loire. ; INCA = PL-BIO 2014–2020 ; consortium MARENGO (MicroRNA agonist and antagonist Nanomedicines for GliOblastoma treatment: from molecular programmation to preclinical validation). ; Région Pays-de-la-Loire & Cancéropole Grand-Ouest : MuMoFRaT project (Multi-scale Modeling & simulation of the response to hypo-Fractionated Radiotherapy or repeated molecular radiation Therapies). ; EUROPE : NanoFar program (European doctorate in nanomedicine and pharmaceutical innovation) (Erasmus Mundus Joint Doctorate) funded by, EACEA ; ANR-11-LABX-0018,IRON,Radiopharmaceutiques Innovants en Oncologie et Neurologie(2011) ; ANR-19-ENM3-0003,GLIOSILK,Silk-fibroin interventional nano-trap for the treatment of glioblastoma.(2019) |
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Zeitschrift: | ISSN: 2296-4185 ; Frontiers in Bioengineering and Biotechnology ; https://inserm.hal.science/inserm-03374695 ; Frontiers in Bioengineering and Biotechnology, 2021, 2021 |
Veröffentlichung: | HAL CCSD ; Frontiers, 2021 |
Medientyp: | academicJournal |
DOI: | 10.3389/fbioe.2020.602998 |
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