期刊
FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY
卷 8, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fbioe.2020.602998
关键词
rapamycin; nanoparticles; radiation; hypoxia; mTOR; Akt; HIF-1 alpha; cancer
资金
- French National Research Agency (ANR) through the LabEx IRON (Innovative Radiopharmaceuticals in Oncology and Neurology), French government Investissements d'Avenir program [ANR-11-LABX-0018]
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- University of Angers (Angers, France)
- NanoFar program (European doctorate in nanomedicine and pharmaceutical innovation) (Erasmus Mundus Joint Doctorate) - EACEA
- NanoFar+ program (International strategy) - La Region Pays-de-la-Loire
- La Region Pays-de-la-Loire
- Canceropole Grand-Ouest (Vectorization, imaging, and radiotherapies network)
- La Region Pays de la Loire
- LabEx IRON-2/University of Angers
- Comite de Loire-Atlantique
The study investigates a novel method for the formulation of safe rapamycin nanocarriers and confirms its potential in cancer treatment. Results show that LNC-rapa selectively inhibits the mTORC1 signaling pathway in the U87MG glioblastoma model. Additionally, there are differences in the mTOR inhibition response to rapamycin under different oxygen concentration conditions.
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 similar to 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 mu M 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-1 alpha in hypoxia.
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