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

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外文摘要：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,thin-ning 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 ampli-fying 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.

外文关键词：

Dendritic prodrugEnhanced penetrationMetabolic interventionCancer-associated fibroblastsImmunogenic cell deathChemotherapyImmunotherapyImmune microenvironment reconstitution

作者：

Yunkun Li、Xiaoding Shen、Haitao Ding、Yuxin Zhang、Dayi Pan、Liping Su、Yahui Wu、Zaixiang Fang、Jie Zhou、Qiyong Gong、Kui Luo

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作者单位：

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

Functional and Molecular Imaging Key Laboratory of Sichuan Province,and Research Unit of Psychoradiology,Chinese Academy of Medical Sciences,Chengdu 610041,China

Department of Radiology,West China Xiamen Hospital of Sichuan University,Xiamen 361021,China

基金：

National Science and Technology Major Project of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Key Research and Development Program of ChinaDepartment of Science and Technology of Sichuan Province,China1-3-5 Project for Disciplines of Excellence,West China Hospital,Sichuan University,ChinaPost-Doctor Research Project,West China Hospital,Sichuan University,ChinaPost-Doctor Research Project,West China Hospital,Sichuan University,ChinaChina Postdoctoral Science Foundation

项目编号：

2023YFB3810004322714455210317532271382321011452022YFC200990024NSFJQ0167ZYJC210132021HXBH0552021HXBH0572021M692314

出版年：

2024

DOI：

10.1016/j.apsb.2024.03.010

药学学报(英文版)

CSTPCD

ISSN：

年,卷(期)：2024.14(8)