Mesyl phosphoramidate backbone modified antisense oligonucleotides targeting miR-21 with enhanced in vivo therapeutic potency

Journal article

The design of modified oligonucleotides that combine in one molecule several therapeutically beneficial properties still poses a major challenge. Recently a new type of modified mesyl phosphoramidate (or µ-) oligonucleotide was described that demonstrates high affinity to RNA, exceptional nuclease resistance, efficient recruitment of RNase H, and potent inhibition of key carcinogenesis processes in vitro. Herein, using a xenograft mouse tumor model, it was demonstrated that microRNA miR-21–targeted µ-oligonucleotides administered in complex with folate-containing liposomes dramatically inhibit primary tumor growth via long-term down-regulation of miR-21 in tumors and increase in biosynthesis of miR-21–regulated tumor suppressor proteins. This antitumoral effect is superior to the effect of the corresponding phosphorothioate. Peritumoral administration of µ-oligonucleotide results in its rapid distribution and efficient accumulation in the tumor. Blood biochemistry and morphometric studies of internal organs revealed no pronounced toxicity of µ-oligonucleotides. This new oligonucleotide class provides a powerful tool for antisense technology.

Authors: Patutina, OA; Gaponova Miroshnichenko, SK; Sen'kova, AV; Savin, IA; Gladkikh, DV

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: National Academy of Sciences
• Journal: Proceedings of the National Academy of Sciences of the United States of America
• Volume: 117
• Issue: 51
• Pages: 32370-32379
• Publication date: 2020-12-07
• Acceptance date: 2020-11-02
• DOI: 10.1073/pnas.2016158117
• EISSN: 1091-6490
• ISSN: 0027-8424
• Pmid: 33288723
• Language: English
• Keywords: phosphoric acids; melanoma; mice, SCID; phosphorothioate; gene expression regulation, neoplastic; molecular targeted therapy; microRNAs; FFR; amides; cell line, tumor; tissue distribution; DNA modification; oligonucleotide, antisense; antineoplastic agents; mesyl oligonucleotide; xenograft model antitumor assays; oncogenic