2'-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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, H-D; Su, C; Kim, JH; Dalton, HJ; Kovvali, C; Keyomarsi, K; McMillan, NAJ; Overwijk, WW; Liu, J; Lee, J-S; Baggerly, KA; Lopez-Berestein, G; Ram, PT; Nawrot, B; Sood, AK

Published Date

  • March 12, 2014

Published In

Volume / Issue

  • 5 /

Start / End Page

  • 3459 -

PubMed ID

  • 24619206

Pubmed Central ID

  • PMC4112501

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/ncomms4459


  • eng

Conference Location

  • England