Systemic and specific delivery of small interfering RNAs to the liver mediated by apolipoprotein A-I.
Tissue-targeted delivery of small interfering RNA (siRNA) must be achieved before RNA interference (RNAi) technology can be used in practical therapeutic approaches. In this study, the potential of apolipoprotein A-I (apo A-I) for the systemic delivery of nucleic acids to the liver is demonstrated using real-time in vivo imaging. As a proof of concept, synthetic siRNAs against hepatitis B virus (HBV) were formulated into complexes of apo A-I and 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)/cholesterol (DTC-Apo) and injected intravenously (i.v.) into a mouse model carrying replicating HBV. We show that administration of these nanoparticles can significantly reduce viral protein expression by receptor-mediated endocytosis. The advantages of the apo A-I-mediated siRNA delivery method are its liver specificity, its effectiveness at low doses (< or = 2 mg/kg) in only a single treatment, and its persistent antiviral effect up to 8 days. The liver-targeted gene silencing was also shown by in vivo images, in which bioluminescent signals emitted from the liver were efficiently reduced after i.v. administration of luciferase-specific siRNA and DTC-Apo lipoplex. Thus, our unique approach to siRNA delivery creates a foundation for the development of a new class of promising therapeutics against hepatitis viruses or hepatocyte genes related to tumor growth.
Kim
Soo In
SI
Immunology and Virology Group, Mogam Biotechnology Research Institute, Yongin-si, South Korea.
Shin
Duckhyang
D
Choi
Tae Hyun
TH
Lee
Jong Chan
JC
Cheon
Gi-Jeong
GJ
Kim
Ki-Yong
KY
Park
Mahnhoon
M
Kim
Meehyein
M
D000818:Animals; D016632:Apolipoprotein A-I / Q000737:chemistry*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006515:Hepatitis B virus / Q000235:genetics; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D010957:Plasmids / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D016632:Apolipoprotein A-I; D005229:Fatty Acids, Monounsaturated; D000644:Quaternary Ammonium Compounds; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D008156:Luciferases; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane