Chen Jitang, Zhang Zhijie, Li Yining, Zeng Haowen, Li Zheng, Wang Chong, Xu Chen, Deng Qingyuan, Wang Qiang, Yang Xiangliang, Li Zifu
National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, P. R. China.
Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, P. R. China.
J Mater Chem B. 2022 Oct 19;10(40):8193-8210. doi: 10.1039/d2tb01812h.
Chemotherapy is a conventional cancer treatment in clinical settings. Although numerous nano drug delivery systems have been developed, the chemotherapeutic effect is greatly limited by abnormal tumor mechanics in solid tumors. Tumor stiffening and accumulated solid stress compress blood vessels and inhibit drug delivery to tumor cells, becoming critical challenges for chemotherapy. By loading doxorubicin (DOX), tissue plasminogen activator (tPA), and fibrin targeting peptide CREKA (Cys-Arg-Glu-Lys-Ala) within pH responsive amphiphilic block polymers, pyridyldithio-hydroxyethyl starch-Schiff base-polylactic acid (PA-HES-pH-PLA), we report a smart nanomedicine, DOX@CREKA/tPA-HES-pH-PLA (DOX@CREKA/tPA-HP), which exhibits a potent antitumor efficacy. In triple-negative breast cancer (TNBC) 4T1 tumors, DOX@CREKA/tPA-HP precisely targeted and effectively decomposed fibrin matrix. By measuring Young's Modulus of tumor slices and quantifying tumor openings, we demonstrated that DOX@CREKA/tPA-HP remarkably reduced tumor stiffness and solid stress. Consequently, the alleviated tumor mechanics decompressed tumor blood vessels, promoted drug delivery, and led to amplified antitumor effect. Our work reveals that decomposing fibrin is a significant means for modulating tumor mechanics, and DOX@CREKA/tPA-HP is a promising smart nanomedicine for treating TNBC.
化疗是临床环境中一种传统的癌症治疗方法。尽管已经开发了许多纳米药物递送系统，但实体瘤中异常的肿瘤力学极大地限制了化疗效果。肿瘤硬化和累积的固体应力会压缩血管并抑制药物向肿瘤细胞的递送，这成为化疗的关键挑战。通过将阿霉素（DOX）、组织纤溶酶原激活剂（tPA）和纤维蛋白靶向肽CREKA（半胱氨酸-精氨酸-谷氨酸-赖氨酸-丙氨酸）负载在pH响应性两亲性嵌段聚合物吡啶二硫代羟乙基淀粉-席夫碱-聚乳酸（PA-HES-pH-PLA）中，我们报道了一种智能纳米药物DOX@CREKA/tPA-HES-pH-PLA（DOX@CREKA/tPA-HP），它具有强大的抗肿瘤功效。在三阴性乳腺癌（TNBC）4T1肿瘤中，DOX@CREKA/tPA-HP能精确靶向并有效分解纤维蛋白基质。通过测量肿瘤切片的杨氏模量并量化肿瘤开口，我们证明DOX@CREKA/tPA-HP显著降低了肿瘤硬度和固体应力。因此，缓解的肿瘤力学减轻了肿瘤血管的压力，促进了药物递送，并导致抗肿瘤效果增强。我们的工作表明，分解纤维蛋白是调节肿瘤力学的重要手段，而DOX@CREKA/tPA-HP是一种有前途的用于治疗TNBC的智能纳米药物。
