Modulating tumor-stromal crosstalk via a redox-responsive nanomedicine for combination tumor therapy

Yuxin Zhang; Jie Zhou; Xiaoting Chen; Zhiqian Li; Lei Gu; Dayi Pan; Xiuli Zheng; Qianfeng Zhang; Rongjun Chen; Hu Zhang; Qiyong Gong; Zhongwei Gu; Kui Luo

doi:10.1016/j.jconrel.2023.03.015

Modulating tumor-stromal crosstalk via a redox-responsive nanomedicine for combination tumor therapy

J Control Release. 2023 Apr:356:525-541. doi: 10.1016/j.jconrel.2023.03.015. Epub 2023 Mar 15.

Authors

Yuxin Zhang¹, Jie Zhou¹, Xiaoting Chen¹, Zhiqian Li¹, Lei Gu¹, Dayi Pan², Xiuli Zheng¹, Qianfeng Zhang¹, Rongjun Chen³, Hu Zhang⁴, Qiyong Gong⁵, Zhongwei Gu¹, Kui Luo⁶

Affiliations

¹ Huaxi MR Research Center (HMRRC), Department of Radiology, Animal Experimental Center, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
² Huaxi MR Research Center (HMRRC), Department of Radiology, Animal Experimental Center, 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, Key Laboratory of Transplant Engineering and Immunology, NHC, and Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu 610041, China.
³ Department of Chemical Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom.
⁴ Amgen Bioprocessing Centre, Keck Graduate Institute, Claremont, CA 91711, USA.
⁵ Huaxi MR Research Center (HMRRC), Department of Radiology, Animal Experimental Center, 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, Key Laboratory of Transplant Engineering and Immunology, NHC, and Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu 610041, China; Department of Radiology, West China Xiamen Hospital of Sichuan University, Xiamen, Fujian, China.
⁶ Huaxi MR Research Center (HMRRC), Department of Radiology, Animal Experimental Center, 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, Key Laboratory of Transplant Engineering and Immunology, NHC, and Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu 610041, China. Electronic address: luokui@scu.edu.cn.

PMID: 36918084
DOI: 10.1016/j.jconrel.2023.03.015

Abstract

Interaction between carcinoma-associated fibroblasts (CAFs) and tumor cells leads to the invasion and metastasis of breast cancer. Herein, we prepared a redox-responsive chondroitin sulfate (CS)-based nanomedicine, in which hydrophobic cabazitaxel (CTX) was conjugated to the backbone of CS via glutathione (GSH)-sensitive dithiomaleimide (DTM) to form an amphipathic CS-DTM-CTX (CDC) conjugate, and dasatinib (DAS) co-assembled with the CDC conjugate to obtain DAS@CDC. After CD44 receptor-mediated internalization by CAFs, the nanomedicine could reverse CAFs to normal fibroblasts, blocking their crosstalk with tumor cells and reducing synthesis of major tumor extracellular matrix proteins, including collagen and fibronectin. Meanwhile, the nanomedicine internalized by tumor cells could effectively inhibit tumor proliferation and metastasis, leading to shrinkage of the tumor volume and inhibition of lung metastasis in a subcutaneous 4T1 tumor model with low side effects. Collectively, the nanomedicine showed a remarkably synergistic therapy effect against breast cancer by modulating tumor-stromal crosstalk.

Keywords: Carcinoma-associated fibroblasts (CAFs); Combination therapy; Polymer-drug conjugate; Stimuli-responsive nanomedicine; Triple-negative breast cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Breast Neoplasms* / pathology
Cell Line, Tumor
Female
Fibroblasts / metabolism
Humans
Nanomedicine*
Oxidation-Reduction
Tumor Microenvironment