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Nat Commun. 2014 Mar 12;5:3459. doi: 10.1038/ncomms4459.

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

Author information

1
1] Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA [2].
2
1] AM Biotechnologies LLC, 12521 Gulf Freeway, Houston, Texas 77034, USA [2].
3
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
4
Department of Biochemistry, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, USA.
5
Division of Cancer Medicine, MDACC, Houston, Texas 77054, USA.
6
Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, Lodz, Poland.
7
1] Department of Experimental Therapeutics, MDACC, Houston, Texas 77054, USA [2] Center for RNA Interference and Non-Coding RNA, MDACC, Houston, Texas 77054, USA.
8
Department of Cancer Biology, MDACC, Houston, Texas 77054, USA.
9
Sigma Life Science, 9186 Six Pines, The Woodlands, Texas 77380, USA.
10
1] Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA [2] Center for RNA Interference and Non-Coding RNA, MDACC, Houston, Texas 77054, USA.
11
Department of Systems Biology, MDACC, Houston, Texas 77054, USA.
12
1] University of Queensland Diamantina Institute, Woolloongabba, Queensland 4102, Australia [2] Centre for Biomolecular Sciences, School of Pharmacy, The University of Nottingham, Nottingham NG7 2RD, UK.
13
1] Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA [2] Center for RNA Interference and Non-Coding RNA, MDACC, Houston, Texas 77054, USA [3] Department of Immunology Laboratory, School of Medicine, Konkuk University, Chungju 380-701, South Korea.
14
1] Department of Systems Biology, MDACC, Houston, Texas 77054, USA [2] Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul 136-701, Korea.
15
Department of Experimental Radiation Oncology, MDACC, Houston, Texas 77054, USA.
16
1] University of Queensland Diamantina Institute, Woolloongabba, Queensland 4102, Australia [2] Griffith Health Institute and School of Medical Sciences, Griffith University, Southport, Queensland 4222, Australia.
17
Department of Melanoma Medical Oncology, MDACC, Houston, Texas 77054, USA.
18
Department of Pathology, MDACC, Houston, Texas 77054, USA.
19
Department of Bioinformatics, MDACC, Houston, Texas 77054, USA.
20
1] Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA [2] Center for RNA Interference and Non-Coding RNA, MDACC, Houston, Texas 77054, USA [3] Department of Cancer Biology, MDACC, Houston, Texas 77054, USA.

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.

PMID:
24619206
PMCID:
PMC4112501
DOI:
10.1038/ncomms4459
[Indexed for MEDLINE]
Free PMC Article

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