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In vitro optimization of 2′-OMe-4′-thioribonucleoside–modified anti-microRNA oligonucleotides and its targeting delivery to mouse liver using a liposomal nanoparticle

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 inhibi...

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Detalles Bibliográficos
Autores principales: Takahashi, Mayumi, Yamada, Naoki, Hatakeyama, Hiroto, Murata, Manami, Sato, Yusuke, Minakawa, Noriaki, Harashima, Hideyoshi, Matsuda, Akira
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905841/
https://www.ncbi.nlm.nih.gov/pubmed/24030710
http://dx.doi.org/10.1093/nar/gkt823
Descripción
Sumario: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.