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 language | English |
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Pages (from-to) | 32370-32379 |
Number of pages | 10 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 117 |
Issue number | 51 |
DOIs | |
Publication status | Published - 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