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

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.

• Authors: Olga A Patutina, Svetlana K Gaponova Miroshnichenko, 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 117 Issue 51 Pg. 32370-32379 (12 22 2020) ISSN: 1091-6490 [Electronic] United States
• PMID: 33288723 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Antineoplastic Agents
• MIRN21 microRNA, human
• MicroRNAs
• Oligonucleotides, Antisense
• Phosphoric Acids
• phosphoramidic acid

Topics

• Amides (chemistry)
• Animals
• Antineoplastic Agents (chemistry, pharmacokinetics, pharmacology)
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic (drug effects)
• Male
• Melanoma (genetics, pathology)
• Mice, SCID
• MicroRNAs (genetics)
• Molecular Targeted Therapy
• Oligonucleotides, Antisense (chemistry, pharmacokinetics, pharmacology)
• Phosphoric Acids (chemistry)
• Tissue Distribution
• Xenograft Model Antitumor Assays