Reversing the PAI-1-induced fibrotic immune exclusion of solid tumor by multivalent CXCR4 antagonistic nano-permeator  

作　　者：Jingwen Dong Chenfei Zhu Ying Huang Quanhao Li Jing Li Zheng Wang Yixin Wang Zhanwei Zhou Minjie Sun 

机构地区：[1]NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients,State Key Laboratory of Natural Medicines,Department of Pharmaceutics,China Pharmaceutical University,Nanjing 210009,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第7期3106-3120,共15页药学学报（英文版）

基　　金：financially supported by the National Key Research and Development Program of China(2017YFA0205402);the National Natural Science Foundation of China(81872817,82102202);Natural Science Foundation of Jiangsu Province(BK20210424,China);the Postdoctoral Innovative Talent Support Program(BX20200387,China)。

摘　　要：Fibrosis is one of the key factors that lead to the immune exclusion of solid tumors.Although degradation of fiber is a promising strategy,its application was still bottlenecked by the side effects of causing metastasis,resulting in the failure of immunotherapy.Here,we developed an antimetastatic polymer(HPA)for the delivery of chemo-drug and antifibrotic siPAI-1 to form the nano-permeator.Nano-permeator shrank after protonation and deeply penetrated into the tumor core to down-regulate the expression of PAI-1 for antifibrosis,and further promoted the sustained infiltration and activation of T cells for killing tumor cells.Moreover,metastasis after fiber elimination was prevented by multivalent CXCR4 antagonistic HPA to reduce the attraction of CXCL12 secreted by distant organs.The administration of stroma-alleviated immunotherapy increased the infiltration of CD8+T cells to 52.5%in tumor tissues,inhibiting nearly 90%metastasis by HPA in distant organs.The nano-permeator reveals the mechanism and correlation between antifibrosis and antimetastasis and was believed to be the optimizing immunotherapy for solid fibrotic tumors.

关 键 词：Immune exclusion PAI-1 Fibrosis Deep penetration AMD3100 CXCR4/CXCL12 Metastasis Immunotherapy 

分 类 号：R730.51[医药卫生—肿瘤]