Li Yunhao, Jia Fan, Gao Yujuan, Wang Xuan, Cui Xinyue, Pan Zian, Wang Weifeng, Li Mingjun, Lu Jianqing, Wu Yan
Department of Medicine, Li Ka Shing Faculty of Medicine, University of HongKong, Hong Kong, China; Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, People's Republic of China.
CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, No. 11 First North Road, Zhongguancun, Beijing 100190, People's Republic of China; University of Chinese Academy of Sciences, Beijing 100049, People's Republic of China.
Int J Biol Macromol. 2023 Apr 1;233:123663. doi: 10.1016/j.ijbiomac.2023.123663. Epub 2023 Feb 11.
Drug resistance in cancer chemotherapy is a major confounding factor affecting the effectiveness of chemotherapeutic agents, thereby leading to poor clinical outcomes. Most chemotherapeutic drugs can induce protective autophagy and increase the resistance of tumors to chemotherapeutic drugs and reduce effective drug delivery to tumor cells. In this study, a tri-drug nanocomposite (NP) delivery system was devised using carboxymethyl β-dextran (CMD) and protamine sulfate (PS), two natural materials with good bio-compatibility. They were designed to carry the chemotherapeutic drug docetaxel (DTX), the autophagy inhibitor chloroquine (CQ), and Atg5 siRNA to cancer cells. The CQ + DTX + Atg5 siRNA NPs was driven by electrostatic interaction and self-assembly methods. The breast cancer cell line MDA-MB-231 was used for both cell culture and establishing mouse xenograft model. Our findings demonstrated that CQ and Atg5 siRNA encapsulated in NPs could enhance the sensitivity of tumor cells to DTX. The NPs exhibited remarkable considerable therapeutic effects for treating triple-negative breast cancer (TNBC) and good biosafety. Therefore, we established a novel multifunctional nanoplatform based on CMD and PS that enhances chemotherapeutic drug sensitivity through an autophagy inhibition strategy, providing new opportunities to overcome conventional drug resistance and enhance therapeutic efficiency against TNBC.
癌症化疗中的耐药性是影响化疗药物疗效的一个主要混杂因素，从而导致临床预后不佳。大多数化疗药物可诱导保护性自噬，增加肿瘤对化疗药物的耐药性，并减少药物向肿瘤细胞的有效递送。在本研究中，利用具有良好生物相容性的两种天然材料——羧甲基β-葡聚糖（CMD）和硫酸鱼精蛋白（PS），设计了一种三药纳米复合（NP）递送系统。它们被设计用于将化疗药物多西他赛（DTX）、自噬抑制剂氯喹（CQ）和Atg5小干扰RNA（siRNA）携带至癌细胞。CQ + DTX + Atg5 siRNA NPs是通过静电相互作用和自组装方法制备的。乳腺癌细胞系MDA-MB-231用于细胞培养和建立小鼠异种移植模型。我们的研究结果表明，包裹在NP中的CQ和Atg5 siRNA可增强肿瘤细胞对DTX的敏感性。这些NPs在治疗三阴性乳腺癌（TNBC）方面表现出显著的治疗效果和良好的生物安全性。因此，我们基于CMD和PS建立了一种新型多功能纳米平台，该平台通过自噬抑制策略增强化疗药物敏感性，为克服传统耐药性和提高TNBC治疗效率提供了新的机会。
