Target delivery of small interfering RNAs with vitamin E-coupled nanoparticles for treating hepatitis C.
RNA interference (RNAi) represents a promising strategy for the treatment of HCV infection. However, the development of an effective system for in vivo delivery of small interfering RNA (siRNA) to target organ remains a formidable challenge. Here, we develop a unique nanoparticle platform (VE-DC) composed of α-tocopherol (vitamin E) and cholesterol-based cationic liposomes (DOTAP-Chol) for systemic delivery of siRNAs to the liver. A HCV-replicable cell line, Huh7.5.1-HCV, and a transient HCV core expressing cell line, Huh7.5.1-Core, were constructed and used to assess the in vitro anti-HCV activity of VE-DC/siRNAs. A transient in vivo HCV model was also constructed by hydrodynamic injection of pCDNA3.1(+)-3FLAG-Core (pCore-3FLAG) plasmid expressing core protein or pGL3-5'UTR-luciferase (pGL3-5'UTR-luc) plasmid expressing luciferase driven by HCV 5'UTR. Nanoscale VE-DC/siRNA was intravenously injected to assess the liver-targeting property as well as antiviral activity. The nanoscale VE-DC effectively exerted an anti-HCV activity in the in vitro cell models. Post-administration of VE-DC/siRNAs also effectively delivered siRNAs to the liver, suppressing core protein production and firefly luciferase activity, without inducing an innate immunity response or off-target and toxicity effects. The VE-DC platform has high potential as a vehicle for delivery of siRNAs to the liver for gene therapy for targeting hepatitis C.
Department of Laboratory Medicine, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
Liang
L
Duan
Department of Laboratory Medicine, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
Yan
Y
Yan
Department of Laboratory Medicine, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
Jingyi
J
Liu
Department of Laboratory Medicine, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
Bo
B
Wang
Department of Laboratory Medicine, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
Pu
P
Li
Department of Laboratory Medicine, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
Qin
Q
Hu
Department of Laboratory Medicine, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
Weixian
W
Chen
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002460:Cell Line; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage*; D006526:Hepatitis C / Q000188:drug therapy*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014810:Vitamin E / Q000008:administration & dosage*
D000998:Antiviral Agents; D004337:Drug Carriers; D008081:Liposomes; D034741:RNA, Small Interfering; D014810:Vitamin E