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

Sherry Y. Wu, Xianbin Yang (), Kshipra M. Gharpure, Hiroto Hatakeyama, Martin Egli, Michael H. McGuire, Archana S. Nagaraja, Takahito M. Miyake, Rajesha Rupaimoole, Chad V. Pecot, Morgan Taylor, Sunila Pradeep, Malgorzata Sierant, Cristian Rodriguez-Aguayo, Hyun J. Choi, Rebecca A. Previs, Guillermo N. Armaiz-Pena, Li Huang, Carlos Martinez, Tom Hassell, Cristina Ivan, Vasudha Sehgal, Richa Singhania, Hee-Dong Han, Chang Su, Ji Hoon Kim, Heather J. Dalton, Chandra Kovvali, Khandan Keyomarsi, Nigel A. J. McMillan, Willem W. Overwijk, Jinsong Liu, Ju-Seog Lee, Keith A. Baggerly, Gabriel Lopez-Berestein, Prahlad T. Ram, Barbara Nawrot and Anil K. Sood ()
Additional contact information
Sherry Y. Wu: The University of Texas MD Anderson Cancer Center (MDACC)
Xianbin Yang: AM Biotechnologies LLC, 12521 Gulf Freeway
Kshipra M. Gharpure: The University of Texas MD Anderson Cancer Center (MDACC)
Hiroto Hatakeyama: The University of Texas MD Anderson Cancer Center (MDACC)
Martin Egli: Vanderbilt University, School of Medicine
Michael H. McGuire: The University of Texas MD Anderson Cancer Center (MDACC)
Archana S. Nagaraja: The University of Texas MD Anderson Cancer Center (MDACC)
Takahito M. Miyake: The University of Texas MD Anderson Cancer Center (MDACC)
Rajesha Rupaimoole: The University of Texas MD Anderson Cancer Center (MDACC)
Chad V. Pecot: MDACC
Morgan Taylor: The University of Texas MD Anderson Cancer Center (MDACC)
Sunila Pradeep: The University of Texas MD Anderson Cancer Center (MDACC)
Malgorzata Sierant: Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences
Cristian Rodriguez-Aguayo: MDACC
Hyun J. Choi: The University of Texas MD Anderson Cancer Center (MDACC)
Rebecca A. Previs: The University of Texas MD Anderson Cancer Center (MDACC)
Guillermo N. Armaiz-Pena: The University of Texas MD Anderson Cancer Center (MDACC)
Li Huang: MDACC
Carlos Martinez: Sigma Life Science
Tom Hassell: Sigma Life Science
Cristina Ivan: The University of Texas MD Anderson Cancer Center (MDACC)
Vasudha Sehgal: MDACC
Richa Singhania: University of Queensland Diamantina Institute
Hee-Dong Han: The University of Texas MD Anderson Cancer Center (MDACC)
Chang Su: The University of Texas MD Anderson Cancer Center (MDACC)
Ji Hoon Kim: MDACC
Heather J. Dalton: The University of Texas MD Anderson Cancer Center (MDACC)
Chandra Kovvali: The University of Texas MD Anderson Cancer Center (MDACC)
Khandan Keyomarsi: MDACC
Nigel A. J. McMillan: University of Queensland Diamantina Institute
Willem W. Overwijk: MDACC
Jinsong Liu: MDACC
Ju-Seog Lee: MDACC
Keith A. Baggerly: MDACC
Gabriel Lopez-Berestein: MDACC
Prahlad T. Ram: MDACC
Barbara Nawrot: Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences
Anil K. Sood: The University of Texas MD Anderson Cancer Center (MDACC)

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: Abstract 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.

Date: 2014
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DOI: 10.1038/ncomms4459

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