Remodeling “cold” tumor immune microenvironment via epigenetic-based therapy using targeted liposomes with in situ formed albumin corona  

作　　者：Yang He Yuefei Fang Meng Zhang Yuge Zhao Bin Tu Mingjie Shi Bahtiyor Muhitdinov Akmal Asrorov Qin Xu Yongzhuo Huang 

机构地区：[1]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [2]University of Chinese Academy of Sciences,Beijing 100049,China [3]Zhongshan Institute for Drug Discovery,Chinese Academy of Sciences,Zhongshan 528437,China [4]Department of Pharmacy,the First Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,China [5]Artemisinin Research Center,Guangzhou University of Chinese Medicine,Guangzhou 510450,China [6]Women’s Hospital,School of Medicine,Zhejiang University,Hangzhou 310006,China [7]Institute of Bioorganic Chemistry,Uzbekistan Academy of Sciences,Tashkent 100125,Uzbekistan [8]National Medical Products Administration,Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients,Shanghai 201203,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第4期2057-2073,共17页药学学报（英文版）

基　　金：This work was supported by National Special Project for Significant Drugs Development(2018ZX09711002-010-002,China);National Natural Science Foundation of China(NSFC)(81925035,82050410361,and 81521005,China);Shanghai Collaborative Innovation Group(Early diagnosis and precise treatment of hemangiomas and vascular malformations,SSMU-ZDCX20180701,China);Shanghai Sci-Tech Innovation Action Plan(19431903100,China);Chinese Academy of Sciences(CAS)PIFI Fellowship(2019PB0076,2020PB0094,China);Belt&Road Young Scientist Award(Shanghai,18430740800,China).

摘　　要：There is a close connection between epigenetic regulation,cancer metabolism,and immunology.The combination of epigenetic therapy and immunotherapy provides a promising avenue for cancer management.As an epigenetic regulator of histone acetylation,panobinostat can induce histone acetylation and inhibit tumor cell proliferation,as well as regulate aerobic glycolysis and reprogram intratumoral immune cells.JQ1 is a BRD4 inhibitor that can suppress PD-L1 expression.Herein,we proposed a chemo-free,epigenetic-based combination therapy of panobinostat/JQ1 for metastatic colorectal cancer.A novel targeted binary-drug liposome was developed based on lactoferrin-mediated binding with the LRP-1 receptor.It was found that the tumor-targeted delivery was further enhanced by in situ formation of albumin corona.The lactoferrin modification and endogenous albumin adsorption contribute a dual-targeting effect on the receptors of both LRP-1 and SPARC that were overexpressed in tumor cells and immune cells(e.g.,tumor-associated macrophages).The targeted liposomal therapy was effective to suppress the crosstalk between tumor metabolism and immune evasion via glycolysis inhibition and immune normalization.Consequently,lactic acid production was reduced and angiogenesis inhibited;TAM switched to an anti-tumor phenotype,and the anti-tumor function of the effector CD8+T cells was reinforced.The strategy provides a potential method for remodeling the tumor immune microenvironment(TIME).

关 键 词：Tumor immune microenvironment Tumor-associated macrophage Epigenetic therapy Immune checkpoint Angiogenesis PANOBINOSTAT JQ1 LIPOSOME 

分 类 号：R730.51[医药卫生—肿瘤]