Zhang Yuxin, Zhou Jie, Chen Xiaoting, Li Zhiqian, Gu Lei, Pan Dayi, Zheng Xiuli, Zhang Qianfeng, Chen Rongjun, Zhang Hu, Gong Qiyong, Gu Zhongwei, Luo Kui
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.
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.
J Control Release. 2023 Apr;356:525-541. doi: 10.1016/j.jconrel.2023.03.015. Epub 2023 Mar 15.
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.
癌相关成纤维细胞（CAFs）与肿瘤细胞之间的相互作用会导致乳腺癌的侵袭和转移。在此，我们制备了一种基于氧化还原响应性硫酸软骨素（CS）的纳米药物，其中疏水性卡巴他赛（CTX）通过谷胱甘肽（GSH）敏感的二硫代马来酰亚胺（DTM）与CS主链偶联，形成两亲性的CS-DTM-CTX（CDC）偶联物，达沙替尼（DAS）与CDC偶联物共组装得到DAS@CDC。在CAFs通过CD44受体介导内化后，该纳米药物可将CAFs逆转成正常成纤维细胞，阻断它们与肿瘤细胞的串扰，并减少包括胶原蛋白和纤连蛋白在内的主要肿瘤细胞外基质蛋白的合成。同时，被肿瘤细胞内化的纳米药物可有效抑制肿瘤增殖和转移，在皮下4T1肿瘤模型中使肿瘤体积缩小并抑制肺转移，且副作用小。总体而言，该纳米药物通过调节肿瘤-基质串扰对乳腺癌显示出显著的协同治疗效果。
