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

Publication ,  Journal Article
Wu, SY; Yang, X; Gharpure, KM; Hatakeyama, H; Egli, M; McGuire, MH; Nagaraja, AS; Miyake, TM; Rupaimoole, R; Pecot, CV; Taylor, M; Pradeep, S ...
Published in: Nat Commun
March 12, 2014

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.

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Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

March 12, 2014

Volume

5

Start / End Page

3459

Location

England

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • RNA-Induced Silencing Complex
  • RNA, Small Interfering
  • Phosphates
  • Mice, Nude
  • Mice
  • Immunohistochemistry
  • Humans
  • Female
  • Cell Line, Tumor
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Wu, S. Y., Yang, X., Gharpure, K. M., Hatakeyama, H., Egli, M., McGuire, M. H., … Sood, A. K. (2014). 2'-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity. Nat Commun, 5, 3459. https://doi.org/10.1038/ncomms4459
Wu, Sherry Y., Xianbin Yang, Kshipra M. Gharpure, Hiroto Hatakeyama, Martin Egli, Michael H. McGuire, Archana S. Nagaraja, et al. “2'-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity.Nat Commun 5 (March 12, 2014): 3459. https://doi.org/10.1038/ncomms4459.
Wu SY, Yang X, Gharpure KM, Hatakeyama H, Egli M, McGuire MH, et al. 2'-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity. Nat Commun. 2014 Mar 12;5:3459.
Wu, Sherry Y., et al. “2'-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity.Nat Commun, vol. 5, Mar. 2014, p. 3459. Pubmed, doi:10.1038/ncomms4459.
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. 2'-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity. Nat Commun. 2014 Mar 12;5:3459.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

March 12, 2014

Volume

5

Start / End Page

3459

Location

England

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • RNA-Induced Silencing Complex
  • RNA, Small Interfering
  • Phosphates
  • Mice, Nude
  • Mice
  • Immunohistochemistry
  • Humans
  • Female
  • Cell Line, Tumor