2'-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity. Nat Commun 2014 Mar 12;5:3459
Date
03/13/2014Pubmed ID
24619206Pubmed Central ID
PMC4112501DOI
10.1038/ncomms4459Scopus ID
2-s2.0-84896259886 (requires institutional sign-in at Scopus site) 106 CitationsAbstract
Improving small interfering RNA (siRNA) efficacy in target cell populations remains a challenge to its clinical implementation. Here, we report a chemical modification, consisting of phosphorodithioate (PS2) and 2'-O-Methyl (2'-OMe) MePS2 on one nucleotide that significantly enhances potency and resistance to degradation for various siRNAs. We find enhanced potency stems from an unforeseen increase in siRNA loading to the RNA-induced silencing complex, likely due to the unique interaction mediated by 2'-OMe and PS2. We demonstrate the therapeutic utility of MePS2 siRNAs in chemoresistant ovarian cancer mouse models via targeting GRAM domain containing 1B (GRAMD1B), a protein involved in chemoresistance. GRAMD1B silencing is achieved in tumours following MePS2-modified siRNA treatment, leading to a synergistic anti-tumour effect in combination with paclitaxel. Given the previously limited success in enhancing siRNA potency with chemically modified siRNAs, our findings represent an important advance in siRNA design with the potential for application in numerous cancer types.
Author List
Wu SY, Yang X, Gharpure KM, Hatakeyama H, Egli M, McGuire MH, Nagaraja AS, Miyake TM, Rupaimoole R, Pecot CV, Taylor M, Pradeep S, Sierant M, Rodriguez-Aguayo C, Choi HJ, Previs RA, Armaiz-Pena GN, Huang L, Martinez C, Hassell T, Ivan C, Sehgal V, Singhania R, Han HD, Su C, Kim JH, Dalton HJ, Kovvali C, Keyomarsi K, McMillan NA, Overwijk WW, Liu J, Lee JS, Baggerly KA, Lopez-Berestein G, Ram PT, Nawrot B, Sood AKAuthor
Sunila Pradeep PhD Associate Professor in the Obstetrics and Gynecology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCell Line, Tumor
Female
Humans
Immunohistochemistry
Mice
Mice, Nude
Phosphates
RNA, Small Interfering
RNA-Induced Silencing Complex
Xenograft Model Antitumor Assays