PT  - JOURNAL ARTICLE
AU  - Zening Zheng
AU  - Jiaxin Zhang
AU  - Jizong Jiang
AU  - Yang He
AU  - Wenyuan Zhang
AU  - Xiaopeng Mo
AU  - Xuejia Kang
AU  - Qin Xu
AU  - Bing Wang
AU  - Yongzhuo Huang
TI  - Remodeling tumor immune microenvironment (TIME) for glioma therapy using multi-targeting liposomal codelivery
AID  - 10.1136/jitc-2019-000207
DP  - 2020 Aug 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - e000207
VI  - 8
IP  - 2
4099  - http://jitc.bmj.com/content/8/2/e000207.short
4100  - http://jitc.bmj.com/content/8/2/e000207.full
SO  - J Immunother Cancer2020 Aug 01; 8
AB  - 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 α7 nicotinic acetylcholine receptors (nAChRs)-binding peptide 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.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.