期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 51, 页码 32370-32379出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2016158117
关键词
antisense oligonucleotide; DNA modification; mesyl oligonucleotide; oncogenic microRNA; phosphorothioate
资金
- Russian Science Foundation [19-74-30011]
- Russian State-funded budget project of Institute of Chemical Biology and Fundamental Medicine SB RAS [AAAA-A17-117020210024-8]
- Russian Foundation for Basic Research [18-51505007, 18-515-57006]
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 mu-) 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 mu-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 mu-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 mu-oligonucleotides. This new oligonucleotide class provides a powerful tool for antisense technology.
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