Virus Laboratory, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China.
Int J Nanomedicine. 2018 Mar 15;13:1539-1552. doi: 10.2147/IJN.S157519. eCollection 2018.
Small interfering RNA (siRNA) as a new therapeutic modality holds promise for cancer treatment. However, the traditional viral carriers are prone to immunogenicity and risk of insertional mutagenesis.
In order to provide a tumor-targeted delivery carrier of siRNA in cancer therapy, the hyaluronic acid (HA)-selenium (Se)-polyethylenimine (PEI) nanoparticle (NP) was fabricated by decorating SeNP with HA as a tumor-targeting moiety and by linking the polycationic polymers polyethylenimine PEI onto the surface of SeNP. The siRNA was loaded to the surface of SeNP HA-Se-PEI via the electrostatic interaction between siRNA and PEI to prepare the functionalized SeNP HA-Se-PEI@siRNA.
The HA-Se-PEI@siRNA was internalized into the HepG2 cell mainly in a clathrin-mediated endocytosis manner. Owing to the active tumor-targeted effect mediated by HA, HA-Se-PEI@siRNA achieved the obvious higher transfection efficiency, greater gene silencing ability, and stronger cytotoxicity in the HepG2 cell compared with the passive tumor-targeted NP Se-PEI@siRNA. The knockdown of hairy and enhancer of split 5 by HA-Se-PEI@siRNA induced the HepG2 cell cycle arrest at the G0/G1 phase and apoptosis. Furthermore, the treatment with HA-Se-PEI@siRNA resulted in greater antitumor efficacy compared with the Se-PEI@siRNA in vitro and in vivo. In addition, the HA-Se-PEI@siRNA was almost no toxic to the key organs of mice.
These findings provided an alternative therapeutic route for targeted cancer treatments.
小干扰 RNA（siRNA）作为一种新的治疗方式，有望应用于癌症治疗。然而，传统的病毒载体易引起免疫原性和插入突变的风险。
为了在癌症治疗中提供一种靶向肿瘤的 siRNA 递药载体，通过将硒纳米颗粒（SeNP）用透明质酸（HA）进行修饰作为肿瘤靶向部分，并将聚阳离子聚合物聚乙烯亚胺（PEI）连接到 SeNP 的表面，制备了透明质酸（HA）-硒（Se）-聚乙烯亚胺（PEI）纳米颗粒（NP）。通过 siRNA 与 PEI 之间的静电相互作用将 siRNA 装载到 SeNPHA-Se-PEI 的表面上，制备了功能化的 SeNPHA-Se-PEI@siRNA。
HA-Se-PEI@siRNA 主要通过网格蛋白介导的内吞作用被内化进入 HepG2 细胞。由于 HA 介导的主动靶向作用，HA-Se-PEI@siRNA 在 HepG2 细胞中实现了更高的转染效率、更强的基因沉默能力和更强的细胞毒性，与被动靶向 NP Se-PEI@siRNA 相比。HA-Se-PEI@siRNA 下调了毛状和分裂增强子 5，导致 HepG2 细胞周期停滞在 G0/G1 期并发生凋亡。此外，HA-Se-PEI@siRNA 的治疗在体外和体内均表现出比 Se-PEI@siRNA 更强的抗肿瘤疗效。此外，HA-Se-PEI@siRNA 对小鼠的关键器官几乎没有毒性。
这些发现为靶向癌症治疗提供了一种替代的治疗途径。
