A neutrophil-biomimic platform for eradicating metastatic breast cancer stem-like cells by redox microenvironment modulation and hypoxia-triggered differentiation therapy  

作　　者：Yongchao Chu Yifan Luo Boyu Su Chao Li Qin Guo Yiwen Zhang Peixin Liu Hongyi Chen Zhenhao Zhao Zheng Zhou Yu Wang Chen Jiang Tao Sun 

机构地区：[1]Key Laboratory of Smart Drug Delivery(Ministry of Education),Minhang Hospital,State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science,Department of Pharmaceutics,School of Pharmacy,Research Center on Aging and Medicine,Fudan University,Shanghai 201203,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第1期298-314,共17页药学学报（英文版）

基　　金：supported by National Natural Science Funds of China(92059110/81872808,China);Development Fund for Shanghai Talents(2020090,China);FDU 2025-Excellence Program Fund(China);Program of Shanghai Academic Research Leader(18XD1400500,China);Project Supported by Shanghai Municipal Science and Technology Major Project(2018SHZDZX01,China);ZJLab。

摘　　要：Metastasis accounts for 90%of breast cancer deaths,where the lethality could be attributed to the poor drug accumulation at the metastatic loci.The tolerance to chemotherapy induced by breast cancer stem cells(BCSCs)and their particular redox microenvironment further aggravate the therapeutic dilemma.To be specific,therapy-resistant BCSCs can differentiate into heterogeneous tumor cells constantly,and simultaneously dynamic maintenance of redox homeostasis promote tumor cells to retro-differentiate into stem-like state in response to cytotoxic chemotherapy.Herein,we develop a specifically-designed biomimic platform employing neutrophil membrane as shell to inherit a neutrophil-like tumor-targeting capability,and anchored chemotherapeutic and BCSCs-differentiating reagents with nitroimidazole(NI)to yield two hypoxia-responsive prodrugs,which could be encapsulated into a polymeric nitroimidazole core.The platform can actively target the lung metastasis sites of triple negative breast cancer(TNBC),and release the escorted drugs upon being triggered by the hypoxia microenvironment.During the responsiveness,the differentiating agent could promote transferring BCSCs into non-BCSCs,and simultaneously the nitroimidazole moieties conjugated on the polymer and prodrugs could modulate the tumor microenvironment by depleting nicotinamide adenine dinucleotide phosphate hydrogen(NADPH)and amplifying intracellular oxidative stress to prevent tumor cells retro-differentiation into BCSCs.In combination,the BCSCs differentiation and tumor microenvironment modulation synergistically could enhance the chemotherapeutic cytotoxicity,and remarkably suppress tumor growth and lung metastasis.Hopefully,this work can provide a new insight in to comprehensively treat TNBC and lung metastasis using a versatile platform.

关 键 词：Metastasis Breast cancer NEUTROPHIL HYPOXIA Cancer stem cell GLUTATHIONE Reactive oxygen species NITROIMIDAZOLE 

分 类 号：R737.9[医药卫生—肿瘤]