Silencing of MEF2D by siRNA Loaded Selenium Nanoparticles for Ovarian Cancer Therapy

Abstract

Changbing Wang,1,2,* Yu Xia,1,3,* Shaochuan Huo,4,5,* Diwen Shou,3 Qing Mei,3 Wenjuan Tang,3 Yinghua Li,1 Hongsheng Liu,6 Yongjian Zhou,3 Bing Zhu1 1Central Laboratory, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510120, People’s Republic of China; 2State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510230, People’s Republic of China; 3Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, People’s Republic of China; 4Department of Orthopedics, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen 518048, People’s Republic of China; 5Shenzhen Research Institute of Guangzhou University of Chinese Medicine, Shenzhen 518048, People’s Republic of China; 6Department of Radiology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510120, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bing ZhuCentral Laboratory, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510120, People’s Republic of ChinaTel [phone]Email [email protected] ZhouDepartment of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, People’s Republic of ChinaTel [phone]Email [email protected]: Delivery of therapeutic small interfering RNA (siRNA) via functionalized nanoparticles holds great promise for cancer therapy. However, developing a safe and efficient delivery carrier of siRNA is a challenging issue.Methods: RGDfC peptide was used to modify the surface of selenium nanoparticles (SeNPs) to synthesize a biocompatible siRNA delivery vehicle (R-SeNPs), and MEF2D-siRNA was loaded onto R-SeNPs to prepare a functionalized selenium nanoparticle R-Se@MEF2D-siRNA. The chemical properties of R-SeNPs were characterized, and the anticancer efficacy as well as related mechanisms of R-Se@MEF2D-siRNA were further explored.Results: R-Se@MEF2D-siRNA was significantly taken up by SKOV3 cells and could enter SKOV3 cells mainly in the clathrin-associated endocytosis way. The result of in vitro siRNA release demonstrated that R-Se@MEF2D-siRNA could release MEF2D-siRNA quicker in a microenvironment simulating a lysosomal environment in tumor cells compared to a normal physiological environment. The results of qRT-PCR assay proved that R-Se@MEF2D-siRNA could effectively silence the expression of the MEF2D gene in SKOV3 cells. R-Se@MEF2D-siRNA remarkably suppressed the proliferation of SKOV3 cells and further triggered its apoptosis. In addition, R-Se@MEF2D-siRNA had the capability to disrupt mitochondrial membrane potential (MMP) in SKOV3 cells and resulted in the overproduction of reactive oxygen species (ROS), indicating that mitochondrial dysfunction and ROS generation played an important role in the apoptosis of SKOV3 cells induced by R-Se@MEF2D-siRNA. In vivo, R-Se@MEF2D-siRNA also exhibited excellent antitumor activity mainly through decreasing tumor cells proliferation and triggering their apoptosis in tumor-bearing nude mice.Conclusion: R-Se@MEF2D-siRNA provides an alternative strategy for ovarian cancer treatment in the clinic.Keywords: ovarian cancer, siRNA delivery, gene therapy, tumor targeting, MEF2D

Keywords

• ovarian cancer
• sirna delivery
• gene therapy
• tumor targeting
• mef2d