Tumor-targeted delivery of siRNA to silence Sox2 gene expression enhances therapeutic response in hepatocellular carcinoma

• Published in: Bioactive materials Vol. 6; no. 5; pp. 1330 - 1340
• Main Authors: Xia, Yu, Tang, Guoyi, Chen, Yi, Wang, Changbing, Guo, Min, Xu, Tiantian, Zhao, Mingqi, Zhou, Yongjian
• Format: Journal Article
• Language: English
• Published: China Elsevier B.V 01.05.2021; KeAi Publishing; KeAi Communications Co., Ltd
• Subjects: Cancer; Gene therapy; Nanoparticle; siRNA delivery; Sox2; siRNA delivery; Sox2; Gene therapy; Nanoparticle; Cancer
• ISSN: 2452-199X; 2452-199X
• DOI: 10.1016/j.bioactmat.2020.10.019

RNA interference (RNAi) is one of the most promising methods for the treatment of malignant tumors. However, developing an efficient biocompatible delivery vector for small interfering RNA (siRNA) remains a challenging issue. This study aimed to prepare a non-viral tumor-targeted carrier, named RGDfC-modified functionalized selenium nanoparticles (RGDfC-SeNPs). RGDfC-SeNPs were used to selectively deliver siSox2 to HepG2 liver cancer cells and tissues for the treatment of hepatocellular carcinoma (HCC). In the current study, RGDfC-SeNPs were successfully synthesized and characterized. It was shown that RGDfC-SeNPs could effectively load siSox2 to prepare an antitumor prodrug RGDfC-Se@siSox2. RGDfC-Se@siSox2 exhibited selective uptake in HepG2 liver cancer cells and LO2 normal liver cells, indicating RGDfC-SeNPs could effectively deliver siSox2 to HepG2 liver cancer cells. RGDfC-Se@siSox2 entered HepG2 cells via clathrin-mediated endocytosis by firstly encircling the cytoplasm and then releasing siSox2 in the lysosomes. RGDfC-Se@siSox2 could effectively silence Sox2 and inhibit the proliferation, migration and invasion of HepG2 cells. RGDfC-Se@siSox2 induced HepG2 cells apoptosis most likely via overproduction of reactive oxygen species and disruption of the mitochondrial membrane potentials. Most importantly, RGDfC-Se@siSox2 significantly inhibited the tumor growth in HepG2 tumor-bearing mice without obvious toxic side effects. These studies indicated that RGDfC-SeNPs may be an ideal gene carrier for delivering siSox2 to HepG2 cells and that RGDfC-Se@siSox2 may be a novel and highly specific gene-targeted prodrug therapy for HCC. [Display omitted] •The biocompatible selenium nanoparticle (RGDfC-SeNPs) selectively deliver siRNA to HepG2 cells.•RGDfC-Se@siSox2 induced HepG2 cells apoptosis most likely via ROS overproduction and disruption of MMP.•RGDfC-Se@siSox2 exhibited excellent in vivo antitumor efficacy without obvious toxic side effect.