Targeted delivery of siRNA against hepatitis C virus by apolipoprotein A-I-bound cationic liposomes.
OBJECTIVE
Hepatitis C virus (HCV) is one of the major human hepatic RNA viruses. Recently, we developed a liver-specific siRNA delivery technology using DTC-Apo composed of cationic liposomes (DTC) and apolipoprotein A-I (apo A-I). Here, we investigated whether DTC-Apo nanoparticles can systemically deliver siRNA into mouse hepatocytes expressing HCV proteins and inhibit their expression efficiently.


METHODS
A transient HCV model was constructed by hydrodynamic injection of plasmid DNA expressing viral structural proteins under hepatic control region and alpha1-antitrypsin promoter elements. Using this model, DTC-Apo containing HCV-core-specific siRNA was intravenously injected to assess antiviral activity as well as the duration of silencing.


RESULTS
Post-administration of DTC-Apo/HCV-specific siRNA at a dose of 2mg siRNA/kg inhibited viral gene expression by 65-75% in the liver on day 2. Improved activity (95% knockdown on day 2) without immunotoxicity was obtained by 2'-OMe-modification at two U sequences on its sense strand. Notably, the gene silencing effect of the modified siRNA was still maintained at day 6, while the unmodified one lost RNAi activity after day 4.


CONCLUSIONS
Our results suggest that DTC-Apo liposome is a highly potential delivery vehicle to transfer therapeutic siRNA especially targeting HCV to the liver.
Kim
Soo In
SI
Virus Research Laboratory, Mogam Biotechnology Research Institute, Giheung-Gu, Gyeonggi-Do, South Korea.
Shin
Duckhyang
D
Lee
Hyeon
H
Ahn
Byung-Yoon
BY
Yoon
Yeup
Y
Kim
Meehyein
M
D000818:Animals; D016632:Apolipoprotein A-I / Q000494:pharmacology*; D002460:Cell Line; D016503:Drug Delivery Systems; D004355:Drug Stability; D005260:Female; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D008081:Liposomes / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis / Q000379:methods; D010957:Plasmids; D034741:RNA, Small Interfering / Q000737:chemistry / Q000494:pharmacology*; D014162:Transfection
D016632:Apolipoprotein A-I; D008081:Liposomes; D034741:RNA, Small Interfering