title: The systemic administration of an anti-miRNA oligonucleotide  encapsulated pH-sensitive liposome results in reduced level of  hepatic microRNA-122 in mice.
abstract: 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 100 nM of AMO122 in YSK05-MEND treated cells, but LFN2k showed toxicity at 50 nM. 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 knockdownofmiR-122andan increase in target genes inthe liver, and a subsequent reduction in plasma cholesterol at a dose of 1mgAMO/kgwhile free AMO122 showed no activity at the same dose. The effect ofAMO122 delivered by YSK05-MEND persisted for over 2 weeks. These results suggest that YSK05-MEND is a promising system for delivering AMOs to the liver.
authors: Hiroto
authors: H
authors: Hatakeyama
authors: Manami
authors: M
authors: Murata
authors: Yusuke
authors: Y
authors: Sato
authors: Mayumi
authors: M
authors: Takahashi
authors: Noriaki
authors: N
authors: Minakawa
authors: Akira
authors: A
authors: Matsuda
authors: Hideyoshi
authors: H
authors: Harashima
mesh_terms: D000818:Animals; D002460:Cell Line; D005260:Female; D020868:Gene Silencing; D006863:Hydrogen-Ion Concentration; D008055:Lipids / Q000737:chemistry; D008081:Liposomes / Q000737:chemistry; D008099:Liver / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000032:analysis / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry; D014162:Transfection
chemical_list: D008055:Lipids; D008081:Liposomes; D035683:MicroRNAs; C544354:Mirn122 microRNA, mouse; D016376:Oligonucleotides, Antisense; D010880:Piperidines; C580570:YSK05