Xu Bei, Zhou Wen, Cheng Lizhi, Zhou Yang, Fang Aiping, Jin Chaohui, Zeng Jun, Song Xiangrong, Guo Xia
Department of Pediatric Hematology/Oncology, Key Laboratory of Birth Defect and Related Disorders of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China.
Department of Otolaryngology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
Front Chem. 2020 Sep 29;8:762. doi: 10.3389/fchem.2020.00762. eCollection 2020.
A major barrier for co-delivery of gene medicine with small molecular chemotherapeutic drugs in solid tumors is the inadequate tumor penetration and transfection. In this study, a novel polymeric nanocarrier with integrated properties of tumor penetration, nuclear targeting, and pH-responsive features was designed, and further used to achieve the synergistic anti-tumor effect of curcumin (CUR) and survivin shRNA (pSUR). The polymeric hybrid nanocarrier was constructed from the FDA-approved polymer PLGA and a novel conjugated triblock polymer W5R4K-PEG-PHIS (WPH). CUR and pSUR were simultaneously encapsulated in the dual-drug-loaded nanoparticles (CUR/pSUR-NPs) by a modified double-emulsion solvent evaporation (W/O/W) method. The obtained nanoparticles exhibited better pharmaceutical properties with a uniform spherical morphology and sustained release manners of CUR and pSUR. Excellent features including preferable cellular uptake, efficient endosomal escape, enhanced tumor penetration, and elevated transfection efficiency were further proven. Additionally, a markedly enhanced anti-tumor efficacy for CUR/shRNA-NPs was achieved on SKOV-3 and Hela cells. The synergistic anti-tumor effect involved the inhibition of tumor cell proliferation, induction of cell apoptosis, and the activation of caspase-3 pathways. This work sets up an innovative co-delivery nanosystem to suppress tumor growth, contributing to the development of a comprehensive nanoparticulate strategy for future clinical applications.
在实体瘤中，基因药物与小分子化疗药物联合递送的一个主要障碍是肿瘤穿透和转染不足。在本研究中，设计了一种具有肿瘤穿透、核靶向和pH响应特性的新型聚合物纳米载体，并进一步用于实现姜黄素（CUR）和生存素短发夹RNA（pSUR）的协同抗肿瘤作用。该聚合物杂化纳米载体由美国食品药品监督管理局（FDA）批准的聚合物聚乳酸-羟基乙酸共聚物（PLGA）和一种新型共轭三嵌段聚合物W5R4K-聚乙二醇-聚组氨酸（WPH）构建而成。通过改进的复乳溶剂蒸发法（W/O/W）将CUR和pSUR同时包裹在载双药纳米粒（CUR/pSUR-NPs）中。所制备的纳米粒呈现出更好的药学性质，具有均匀的球形形态以及CUR和pSUR的缓释方式。进一步证明了其具有良好的细胞摄取、有效的内体逃逸、增强的肿瘤穿透和提高的转染效率等优异特性。此外，CUR/shRNA-NPs对SKOV-3和Hela细胞具有显著增强的抗肿瘤功效。这种协同抗肿瘤作用涉及抑制肿瘤细胞增殖、诱导细胞凋亡以及激活半胱天冬酶-3途径。这项工作建立了一种创新的联合递送纳米系统来抑制肿瘤生长，为未来临床应用的综合纳米颗粒策略的发展做出了贡献。
