The systemic administration of an anti-miRNA oligonucleotide encapsulated pH-sensitive liposome results in reduced level of hepatic microRNA-122 in mice

Efficient delivery continues to be a challenge in microRNA (miRNA) therapeutics. We utilized a pH-sensitive multifunctional envelope-type nano device (MEND) containing a pH-sensitive lipid YSK05 (YSK05-MEND) to regulate liver specific miRNA-122 (miR-122). Anti-microRNA oligonucleotides including 2′-...

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Bibliographic Details
Published in:Journal of controlled release 2014-01, Vol.173, p.43-50
Main Authors: Hatakeyama, Hiroto, Murata, Manami, Sato, Yusuke, Takahashi, Mayumi, Minakawa, Noriaki, Matsuda, Akira, Harashima, Hideyoshi
Format: Article
Language:English
Subjects:
Animals
Antisense oligonucleotide
Cell Line
Drug delivery system
Female
Gene Silencing
Hydrogen-Ion Concentration
Lipids - chemistry
Liposomes
Liposomes - chemistry
Liver - metabolism
Mice
MicroRNAs - analysis
MicroRNAs - genetics
miR-122
miRNA
Oligonucleotides, Antisense - administration & dosage
Oligonucleotides, Antisense - pharmacology
Piperidines - chemistry
Transfection
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Summary:Efficient delivery continues to be a challenge in microRNA (miRNA) therapeutics. We utilized a pH-sensitive multifunctional envelope-type nano device (MEND) containing a pH-sensitive lipid YSK05 (YSK05-MEND) to regulate liver specific miRNA-122 (miR-122). Anti-microRNA oligonucleotides including 2′-OMe and phosphorothioate modifications against miR-122 (AMO122) were encapsulated in the YSK05-MEND. Despite the lower uptake, the YSK05-MEND showed a higher activity in liver cancer cells than Lipofectamine2000 (LFN2k) due to efficient endosomal escape. Cytotoxicity was minimal at 100nM of AMO122 in YSK05-MEND treated cells, but LFN2k showed toxicity at 50nM. When mice were administrated with free AMO122, it was eliminated via the kidney due to its molecular weight, and lesser amounts were detected in the liver. Conversely, the YSK05-MEND delivered higher amounts of the AMO122 to the liver. Systemic administration of YSK05-MEND induced the knockdown of miR-122 and an increase in target genes in the liver, and a subsequent reduction in plasma cholesterol at a dose of 1mg AMO/kg while free AMO122 showed no activity at the same dose. The effect of AMO122 delivered by YSK05-MEND persisted for over 2weeks. These results suggest that YSK05-MEND is a promising system for delivering AMOs to the liver. [Display omitted]
ISSN:0168-3659
1873-4995
DOI:10.1016/j.jconrel.2013.10.023