title: 2'-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity.
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.
authors.affiliation: 1] Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA [2].
authors.forename: Sherry Y
authors.initials: SY
authors.lastname: Wu
authors.affiliation: 1] AM Biotechnologies LLC, 12521 Gulf Freeway, Houston, Texas 77034, USA [2].
authors.forename: Xianbin
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
authors.forename: Kshipra M
authors.initials: KM
authors.lastname: Gharpure
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Hatakeyama
authors.affiliation: Department of Biochemistry, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Egli
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: McGuire
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
authors.forename: Archana S
authors.initials: AS
authors.lastname: Nagaraja
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
authors.forename: Takahito M
authors.initials: TM
authors.lastname: Miyake
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
authors.forename: Rajesha
authors.initials: R
authors.lastname: Rupaimoole
authors.affiliation: Division of Cancer Medicine, MDACC, Houston, Texas 77054, USA.
authors.forename: Chad V
authors.initials: CV
authors.lastname: Pecot
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
authors.forename: Morgan
authors.initials: M
authors.lastname: Taylor
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
authors.forename: Sunila
authors.initials: S
authors.lastname: Pradeep
authors.affiliation: Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, Lodz, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Sierant
authors.affiliation: 1] Department of Experimental Therapeutics, MDACC, Houston, Texas 77054, USA [2] Center for RNA Interference and Non-Coding RNA, MDACC, Houston, Texas 77054, USA.
authors.forename: Cristian
authors.initials: C
authors.lastname: Rodriguez-Aguayo
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
authors.forename: Hyun J
authors.initials: HJ
authors.lastname: Choi
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Previs
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
authors.forename: Guillermo N
authors.initials: GN
authors.lastname: Armaiz-Pena
authors.affiliation: Department of Cancer Biology, MDACC, Houston, Texas 77054, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Huang
authors.affiliation: Sigma Life Science, 9186 Six Pines, The Woodlands, Texas 77380, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Martinez
authors.affiliation: Sigma Life Science, 9186 Six Pines, The Woodlands, Texas 77380, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Hassell
authors.affiliation: 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.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ivan
authors.affiliation: Department of Systems Biology, MDACC, Houston, Texas 77054, USA.
authors.forename: Vasudha
authors.initials: V
authors.lastname: Sehgal
authors.affiliation: 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.
authors.forename: Richa
authors.initials: R
authors.lastname: Singhania
authors.affiliation: 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.
authors.forename: Hee-Dong
authors.initials: HD
authors.lastname: Han
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
authors.forename: Chang
authors.initials: C
authors.lastname: Su
authors.affiliation: 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.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Dalton
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
authors.forename: Chandra
authors.initials: C
authors.lastname: Kovvali
authors.affiliation: Department of Experimental Radiation Oncology, MDACC, Houston, Texas 77054, USA.
authors.forename: Khandan
authors.initials: K
authors.lastname: Keyomarsi
authors.affiliation: 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.
authors.forename: Nigel A J
authors.initials: NA
authors.lastname: McMillan
authors.affiliation: Department of Melanoma Medical Oncology, MDACC, Houston, Texas 77054, USA.
authors.forename: Willem W
authors.initials: WW
authors.lastname: Overwijk
authors.affiliation: Department of Pathology, MDACC, Houston, Texas 77054, USA.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Systems Biology, MDACC, Houston, Texas 77054, USA.
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Bioinformatics, MDACC, Houston, Texas 77054, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Baggerly
authors.affiliation: 1] Department of Experimental Therapeutics, MDACC, Houston, Texas 77054, USA [2] Center for RNA Interference and Non-Coding RNA, MDACC, Houston, Texas 77054, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.affiliation: Department of Systems Biology, MDACC, Houston, Texas 77054, USA.
authors.forename: Prahlad T
authors.initials: PT
authors.lastname: Ram
authors.affiliation: Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, Lodz, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Nawrot
authors.affiliation: 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.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D010710:Phosphates / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000737:chemistry* / Q000627:therapeutic use; D034743:RNA-Induced Silencing Complex / Q000737:chemistry* / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D010710:Phosphates; D034741:RNA, Small Interfering; D034743:RNA-Induced Silencing Complex; C083120:phosphorodithioic acid