期刊
JOURNAL FOR IMMUNOTHERAPY OF CANCER
卷 8, 期 2, 页码 -出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/jitc-2019-000207
关键词
tumor microenvironment; macrophages; brain neoplasms; immunotherapy
资金
- NFSC [81925035, 81673382, 81521005]
- Strategic Priority Research Program of CAS [XDA12050307]
- National Special Project for Significant New Drugs Development [2018Zx09711002-010-002]
- Shanghai SciTech Innovation Initiative [19431903100, 18430740800]
- Fudan-SIMM Joint Research Fund [FU-SIMM20174009]
Background Glioblastoma (GBM) treatment is undermined by the suppressive tumor immune microenvironment (TIME). Seek for effective methods for brain TIME modulation is a pressing need. However, there are two major challenges against achieving the goal: first, to screen the effective drugs with TIME-remodeling functions and, second, to develop a brain targeting system for delivering the drugs. Methods In this study, an alpha 7 nicotinic acetylcholine receptors (nAChRs)-binding peptide(D)CDX was used to modify the codelivery liposomes to achieve a 'three-birds-one-stone' delivery strategy, that is, multi-targeting the glioma vessel endothelium, glioma cells, and tumor-associated macrophages that all overexpressed alpha 7 nAChRs. A brain-targeted liposomal honokiol and disulfiram/copper codelivery system (CDX-LIPO) was developed for combination therapy via regulating mTOR (mammalian target of rapamycin) pathway for remodeling tumor metabolism and TIME. Honokiol can yield a synergistic effect with disulfiram/copper for anti-GBM. Results It was demonstrated that CDX-LIPO remarkably triggered tumor cell autophagy and induced immunogenic cell death, and meanwhile, activated the tumor-infiltrating macrophage and dendritic cells, and primed T and NK (natural killer) cells, resulting in antitumor immunity and tumor regression. Moreover, CDX-LIPO promoted M1-macrophage polarization and facilitated mTOR-mediated reprogramming of glucose metabolism in glioma. Conclusion This study developed a potential combinatory therapeutic strategy by regulation of TIME and a 'three-birds-one-stone'-like glioma-targeting drug delivery system.
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