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 via 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 via 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 in vivo. 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.

中文翻译：

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叶酸靶向硒纳米颗粒提供治疗性 siRNA 以改善肝细胞癌治疗†

为了获得用于肝细胞癌治疗的肿瘤靶向 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) 装饰硒纳米粒子来制备功能化的硒纳米粒子 Se-PEI-FA。FA 作为肿瘤靶向分子增强肿瘤靶向活性，PEI 与 FA 和 siRNA 结合。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 的积极肿瘤靶向有效性，与 Se-PEI@siRNA 相比，Se-PEI-FA@siRNA 在 HepG2 细胞中具有显着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 沉默 HES5 可能通过以下途径诱导 HepG2 细胞停滞在 G0/G1 期抑制CDK2、cyclinE和cyclinD1蛋白表达，上调p21蛋白表达。更重要的是，与 Se-PEI@siRNA 相比，Se-PEI-FA@siRNA在体内表现出更显着的抗肿瘤功效。此外，Se-PEI-FA@siRNA 对荷瘤小鼠的重要器官具有低毒性。该研究为设计针对肝细胞癌的肿瘤靶向纳米药物提供了有效的策略。