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

Olga A. Patutina, Svetlana K. Gaponova, Aleksandra V. Sen'kova, Innokenty A. Savin, Daniil V. Gladkikh, Ekaterine A. Burakova, Alesya A. Fokina, Mikhail A. Maslov, Elena V. Shmendel', Mattew J.A. Wood, Valentin V. Vlassov, Sidney Altman, Dmitry A. Stetsenko, Marina A. Zenkova

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)32370-32379
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number51
DOIs
Publication statusPublished - 22 Dec 2020

Keywords

  • Antisense oligonucleotide
  • DNA modification
  • Mesyl oligonucleotide
  • Oncogenic microRNA
  • Phosphorothioate
  • HEPATOCYTES
  • oncogenic microRNA
  • TRAFFICKING
  • PROLIFERATION
  • TOXICITY
  • CELLULAR UPTAKE
  • NUCLEIC-ACIDS
  • DELIVERY
  • antisense oligonucleotide
  • phosphorothioate
  • SIGNALING PATHWAY
  • mesyl oligonucleotide
  • HEPATOTOXICITY
  • DERIVATIVES

OECD FOS+WOS

  • 1.07 OTHER NATURAL SCIENCES

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