Xia Yu, Zhao Mingqi, Chen Yi, Hua Liang, Xu Tiantian, Wang Changbing, Li Yinghua, Zhu Bing
Virus Laboratory, Guangzhou Institute of Paediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University Guangzhou 510120 China.
RSC Adv. 2018 Jul 19;8(46):25932-25940. doi: 10.1039/c8ra04204g.
To obtain a tumor targeting siRNA delivery vehicle for hepatocellular carcinoma treatments, functionalized selenium nanoparticles, Se-PEI-FA, were first prepared by decorating selenium nanoparticles with polycationic polymers, polyethylenimine (PEI), linked with folic acid (FA). FA functions as the tumor-targeted molecule to enhance tumor targeting activity, and PEI conjugates FA and siRNA. Se-PEI-FA@siRNA entered HepG2 cells principally clathrin-mediated endocytosis. Due to the active tumor targeting effectiveness of FA, Se-PEI-FA@siRNA has significantly higher cellular uptake and gene silencing efficiency, and more apparent cytotoxicity, in HepG2 cells compared with Se-PEI@siRNA. The silencing of HES5 by Se-PEI-FA@siRNA could induce HepG2 cells arrest at G0/G1 phase possibly inhibiting protein expression of CDK2, cyclinE, and cyclinD1, and up-regulating the protein expression of p21. More importantly, Se-PEI-FA@siRNA exhibits more significant antitumor efficacy compared with Se-PEI@siRNA . Additionally, Se-PEI-FA@siRNA exhibits low toxicity to the important organs of tumor-bearing mice. This research provides an effective strategy for the design of tumor-targeted nanodrugs against hepatocellular carcinoma.
为了获得用于肝细胞癌治疗的肿瘤靶向性小干扰RNA（siRNA）递送载体，首先通过用与叶酸（FA）连接的聚阳离子聚合物聚乙烯亚胺（PEI）修饰硒纳米颗粒，制备了功能化的硒纳米颗粒Se-PEI-FA。FA作为肿瘤靶向分子发挥作用，以增强肿瘤靶向活性，并且PEI将FA与siRNA偶联。Se-PEI-FA@siRNA主要通过网格蛋白介导的内吞作用进入HepG2细胞。由于FA具有活跃的肿瘤靶向效能，与Se-PEI@siRNA相比，Se-PEI-FA@siRNA在HepG2细胞中具有显著更高的细胞摄取和基因沉默效率，以及更明显的细胞毒性。Se-PEI-FA@siRNA对HES5的沉默可能通过抑制CDK2、细胞周期蛋白E和细胞周期蛋白D1的蛋白表达，并上调p21的蛋白表达，从而诱导HepG2细胞停滞在G0/G1期。更重要的是，与Se-PEI@siRNA相比，Se-PEI-FA@siRNA表现出更显著的抗肿瘤功效。此外，Se-PEI-FA@siRNA对荷瘤小鼠的重要器官表现出低毒性。本研究为设计针对肝细胞癌的肿瘤靶向纳米药物提供了一种有效策略。
