title: In vitro optimization of 2'-OMe-4'-thioribonucleoside-modified anti-microRNA oligonucleotides and its targeting delivery to mouse liver using a liposomal nanoparticle.
abstract: MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression post-transcriptionally. Previous studies, which characterized miRNA function, revealed their involvement in fundamental biological processes. Importantly, miRNA expression is deregulated in many human diseases. Specific inhibition of miRNAs using chemically modified anti-miRNA oligonucleotides (AMOs) can be a potential therapeutic strategy for diseases in which a specific miRNA is overexpressed. 2'-O-Methyl (2'-OMe)-4'-thioRNA is a hybrid type of chemically modified oligonucleotide, exhibiting high binding affinity to complementary RNAs and high resistance to nuclease degradation. Here, we evaluate 2'-OMe-4'-thioribonucleosides for chemical modification on AMOs. Optimization of the modification pattern using a variety of chemically modified AMOs that are perfectly complementary to mature miR-21 revealed that the uniformly 2'-OMe-4'-thioribonucleoside-modified AMO was most potent. Further investigation showed that phosphorothioate modification contributed to long-term miR-122 inhibition by the 2'-OMe-4'-thioribonucleoside-modified AMO. Moreover, systemically administrated AMOs to mouse using a liposomal delivery system, YSK05-MEND, showed delivery to the liver and efficient inhibition of miR-122 activity at a low dose in vivo.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan and Graduate School of Pharmaceutical Sciences, The University of Tokushima, Shomachi 1-78-1, Tokushima 770-8505, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Takahashi
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamada
authors.forename: Hiroto
authors.initials: H
authors.lastname: Hatakeyama
authors.forename: Manami
authors.initials: M
authors.lastname: Murata
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.forename: Noriaki
authors.initials: N
authors.lastname: Minakawa
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuda
mesh_terms: D000818:Animals; D002460:Cell Line; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008081:Liposomes; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000037:antagonists & inhibitors*; D053758:Nanoparticles; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000737:chemistry*; D013872:Thionucleosides / Q000737:chemistry*
chemical_list: D008081:Liposomes; D035683:MicroRNAs; D009841:Oligonucleotides; D013872:Thionucleosides
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