Dendritic nanomedicine enhances chemoimmunotherapy by disturbing metabolism of cancer-associated fibroblasts for deep penetration and activating function of immune cells  

作　　者：Yunkun Li Xiaoding Shen Haitao Ding Yuxin Zhang Dayi Pan Liping Su Yahui Wu Zaixiang Fang Jie Zhoua Qiyong Gong Kui Luo 

机构地区：[1]Department of Radiology,Huaxi MR Research Center(HMRRC),Frontiers Science Center for Disease-Related Molecular Network,State Key Laboratory of Biotherapy,West China Hospital,Sichuan University,Chengdu 610041,China [2]Functional and Molecular Imaging Key Laboratory of Sichuan Province,and Research Unit of Psychoradiology,Chinese Academy of Medical Sciences,Chengdu 610041,China [3]Department of Radiology,West China Xiamen Hospital of Sichuan University,Xiamen 361021,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第8期3680-3696,共17页药学学报（英文版）

基　　金：supported by the National Science and Technology Major Project of China(2023YFB3810004);the National Natural Science Foundation of China(32271445,52103175,32271382,32101145);the National Key Research and Development Program of China(2022YFC2009900);Department of Science and Technology of Sichuan Province(24NSFJQ0167,China);1·3·5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYJC21013,China);Post-Doctor Research Project,West China Hospital,Sichuan University(2021HXBH055,2021HXBH057,China);China Postdoctoral Science Foundation(2021M692314).

摘　　要：Inefficient drug penetration hurdled by the stroma in the tumor tissue leads to a diminished therapeutic effect for drugs and a reduced infiltration level of immune cells.Herein,we constructed a PEGylated dendritic epirubicin(Epi)prodrug(Epi-P4D)to regulate the metabolism of cancer-associated fibroblasts(CAFs),thus enhancing Epi penetration into both multicellular tumor spheroids(MTSs)and tumor tissues in mouse colon cancer(CT26),mouse breast cancer(4T1)and human breast cancer(MDA-MB-231)models.Enhanced cytotoxicity against CT26 MTSs and remarkable antitumor efficacy of Epi-P4D were ascribed to reduced fibronectin,α-SMA,and collagen secretion.Besides,thinning of the tumor tissue stroma and efficient eradication of tumor cells promoted the immunogenic cell death effect for dendritic cell(DC)maturation and subsequent immune activation,including elevating the CD4^(+)T cell population,reducing CD4^(+)and CD8^(+)T cell hyperactivation and exhaustion,and amplifying the natural killer(NK)cell proportion and effectively activating them.As a result,this dendritic nanomedicine thinned the stroma of tumor tissues to enhance drug penetration and facilitate immune cell infiltration for elevated antitumor efficacy.

关 键 词：Dendritic prodrug Enhanced penetration Metabolic intervention Cancer-associated fibroblasts Immunogenic cell death Chemotherapy Immunotherapy Immune microenvironment reconstitution 

分 类 号：R730.51[医药卫生—肿瘤]