Remodeling tumor immune microenvironment (TIME) for glioma therapy using multi-targeting liposomal codelivery

Zening Zheng, Jiaxin Zhang, Jizong Jiang, Yang He, Wenyuan Zhang, Xiaopeng Mo, Xuejia Kang, Qin Xu, Bing Wang, Yongzhuo Huang
2020 Journal for ImmunoTherapy of Cancer  
BackgroundGlioblastoma (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.MethodsIn this study, an α7 nicotinic acetylcholine receptors (nAChRs)-binding peptide DCDX was used to
more » ... DCDX 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 α7 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.ResultsIt 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.ConclusionThis study developed a potential combinatory therapeutic strategy by regulation of TIME and a 'three-birds-one-stone'-like glioma-targeting drug delivery system.
doi:10.1136/jitc-2019-000207 pmid:32817393 fatcat:owdtjaqttbgdvn3zhhrz5bgmrm