Targeting of the nuclease-resistant functional oligonucleotides

2014 Fiscal Year Final Research Report

• Project/Area Number: 23249008
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Hokkaido University
• Principal Investigator: MATSUDA Akira 北海道大学, 薬学研究科(研究院), その他 (90157313)
• Co-Investigator(Renkei-kenkyūsha): SATO Kosuke 北海道大学, 大学院薬学研究院, 助教 (70415686) ; SATO Yusuke 北海道大学, 大学院薬学研究院, 特任助教 (10735624)
• Project Period (FY): 2011-04-01 – 2015-03-31
• Keywords: 核酸医薬 / 組織標的化 / PSMA / オリゴヌクレオチド / ヌクレアーゼ抵抗性 / SPAAC / DNMT1 / stat3

Outline of Final Research Achievements

(1) MicroRNA (miR)-122 is highly expressed in liver and controls cholesterol metabolism. We prepared antisense molecules (AMO) against miR-122 using nuclease resistant 2’-OMe-4’-thioribonucleosides. YSK05-liposome was prepared with the pH-sensitive cationic lipid, and the AMO was encapsulated. Systemic administration of the liposome induced knockdown of miR-122 and increase in target genes in the liver, and a subsequent reduction in plasma cholesterol at a dose of 1mg AMO/kg with persisting for over 2 weeks. (2) Prostate-specific membrane antigen (PSMA) ligand (GL) was attached to a dumbbell-type of the cyclic oligonucleotide (fCpG-dmDNA), which contained 5-formylCpG, giving GL-fCpG-dmDNA. fCpG-dmDNA inhibited the methylation of CpG-oligonucleotides. fCpG-dmDNA showed cytotoxicity against HeLa cells (PSMA-negative) with an IC50 value of 41 nM. On the other hand, GL-fCpG-dmDNA showed cytotoxicity against only PSMA-positive cell line such as LNCaP prostate tumor cells.

Free Research Field

核酸化学