ArticleNature communications2014
2'-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity.
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Article in Nature communications, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers.
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68citing papers in PubMed
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Who cites it
68 citing papers in PubMed, 134 citations in OpenAlex.
- Chemical Modification Strategies for Therapeutic Oligonucleotides: Mechanism Compatibility, Design Trade-Offs, and Translational Barriers.Molecules (Basel, Switzerland) · 2026Review
- 5'-end uridine-derived base modification for siRNAs potency reinforcement.Cell & bioscience · 2026Article
- Electrochemical Phosphorochalcogenations for the Synthesis of Phosphorochalcogenothioates.The Journal of organic chemistry · 2026Article
- Organelle contact sites in cancer cells.Cell death & disease · 2026Review
- A Long-Term Human Liver Spheroid Model for Assessing Silencing and Durability of GalNAc-Conjugated siRNAs.Clinical and translational science · 2026Article
- Unleashing lncRNA THOR: roles in cancer progression and clinical outlook.Molecular genetics and genomics : MGG · 2026Review
- Nucleic acid therapeutics in neurodegenerative disorders: emerging technologies and clinical landscape.Molecular neurodegeneration advances · 2026Review
- Optimized chemical structure extends silencing duration of therapeutic siRNAs in dividing cancer and immune cells.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- RNA chemistry and therapeutics.Nature reviews. Drug discovery · 2025Review
- Small Interfering RNA Carriers for Oncotherapy: A Preclinical Overview.Pharmaceutics · 2025Review
- Landscape of small nucleic acid therapeutics: moving from the bench to the clinic as next-generation medicines.Signal transduction and targeted therapy · 2025Review
- Cesium Carbonate-Catalyzed OxidativeThe Journal of organic chemistry · 2025Article
- Development and evaluation of siRNA-mediated gene silencing strategies for ADO2 therapy utilizing iPSCs model and DMPC-SPIONs delivery system.Stem cell research & therapy · 2025Article
- Small nucleic acid drugs-the dawn of functional cure of chronic hepatitis B.Frontiers in pharmacology · 2025Review
- The beauty of symmetry: siRNA phosphorodithioate modifications reduce stereocomplexity, ease analysis, and can improveMolecular therapy. Nucleic acids · 2024Article
- Lipid nanoparticle-encapsulated DOCK11-siRNA efficiently reduces hepatitis B virus cccDNA level in infected mice.Molecular therapy. Methods & clinical development · 2024Article
- The Impact of Chemical Modifications on the Interferon-Inducing and Antiproliferative Activity of Short Double-Stranded Immunostimulating RNA.Molecules (Basel, Switzerland) · 2024Article
- Assembling the RNA therapeutics toolbox.Medical review (2021) · 2024Review
- MiR-4646-5p Acts as a Tumor-Suppressive Factor in Triple Negative Breast Cancer and Targets the Cholesterol Transport Protein GRAMD1B.Non-coding RNA · 2023Article
- Engineering siRNA therapeutics: challenges and strategies.Journal of nanobiotechnology · 2023Review
8 more citing papers are in PubMed but not listed here.
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Authors and funding
38 authors at 8 institutions in 3 countries.
Sherry Y Wu1] Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA [2].
Xianbin Yang1] AM Biotechnologies LLC, 12521 Gulf Freeway, Houston, Texas 77034, USA [2].
Kshipra M GharpureDepartment of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
Hiroto HatakeyamaDepartment of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
Martin EgliDepartment of Biochemistry, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, USA.
Michael H McGuireDepartment of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
Archana S NagarajaDepartment of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
Takahito M MiyakeDepartment of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
Rajesha RupaimooleDepartment of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
Chad V PecotDivision of Cancer Medicine, MDACC, Houston, Texas 77054, USA.
Morgan TaylorDepartment of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
Sunila PradeepDepartment of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
Malgorzata SierantDepartment of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, Lodz, Poland.
Cristian Rodriguez-Aguayo1] Department of Experimental Therapeutics, MDACC, Houston, Texas 77054, USA [2] Center for RNA Interference and Non-Coding RNA, MDACC, Houston, Texas 77054, USA.
Hyun J ChoiDepartment of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
Rebecca A PrevisDepartment of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
Guillermo N Armaiz-PenaDepartment of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
Li HuangDepartment of Cancer Biology, MDACC, Houston, Texas 77054, USA.
Carlos MartinezSigma Life Science, 9186 Six Pines, The Woodlands, Texas 77380, USA.
Tom HassellSigma Life Science, 9186 Six Pines, The Woodlands, Texas 77380, USA.
Cristina Ivan1] 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.
Vasudha SehgalDepartment of Systems Biology, MDACC, Houston, Texas 77054, USA.
Richa Singhania1] 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.
Hee-Dong Han1] 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.
Chang SuDepartment of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
Ji Hoon Kim1] 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.
Heather J DaltonDepartment of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
Chandra KovvaliDepartment of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas 77054, USA.
Khandan KeyomarsiDepartment of Experimental Radiation Oncology, MDACC, Houston, Texas 77054, USA.
Nigel A J McMillan1] University of Queensland Diamantina Institute, Woolloongabba, Queensland 4102, Australia [2] Griffith Health Institute and School of Medical Sciences, Griffith University, Southport, Queensland 4222, Australia.
Willem W OverwijkDepartment of Melanoma Medical Oncology, MDACC, Houston, Texas 77054, USA.
Jinsong LiuDepartment of Pathology, MDACC, Houston, Texas 77054, USA.
Ju-Seog LeeDepartment of Systems Biology, MDACC, Houston, Texas 77054, USA.
Keith A BaggerlyDepartment of Bioinformatics, MDACC, Houston, Texas 77054, USA.
Gabriel Lopez-Berestein1] Department of Experimental Therapeutics, MDACC, Houston, Texas 77054, USA [2] Center for RNA Interference and Non-Coding RNA, MDACC, Houston, Texas 77054, USA.
Prahlad T RamDepartment of Systems Biology, MDACC, Houston, Texas 77054, USA.
Barbara NawrotDepartment of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, Lodz, Poland.
Anil K Sood1] 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.
The University of Texas MD Anderson Cancer Center · USSigma Technologies (United States) · USUniversity of Queensland · AUCentrum Badań Molekularnych i Makromolekularnych Polskiej Akademii Nauk · PLPolish Academy of Sciences · PLRaptamer Discovery Group (United States) · USTherapeuticsMD (United States) · USVanderbilt University · US
Funding
Tumor Evolution and Metastasis ProgramP30CA016672 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Scott Kopetz · 1985 to 2026
$290.8MUNIVERSITY OF TEXAS MD ANDERSON SPORE IN OVARIAN CANCERP50CA083639 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI BAST, ROBERT C · 1999 to 2015
$33.0MTargeting the PI3K Signaling Pathway in Endometrial CarcinomaP50CA098258 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI BODURKA, DIANE · 2003 to 2020
$32.0MTexas Center for Cancer NanomedicineU54CA151668 · NCI · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI FERRARI, MAURO · 2010 to 2014
$12.4MCenter for Systems Analysis of the Cancer RegulomeU24CA143835 · NCI · INSTITUTE FOR SYSTEMS BIOLOGY · PI SHMULEVICH, ILYA · 2009 to 2016
$10.6MTraining of Academic Gynecologic OncologistsT32CA101642 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI ANIL K SOOD, Kathleen Schmeler · 2005 to 2026
$9.2MOvarian Cancer: Mechanisms of Neuroendocrine RegulationR01CA109298 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI SOOD, ANIL K · 2005 to 2017
$4.5MProteolytic Processing of Cyclin E in Breast CancerR01CA087548 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI KEYOMARSI, KHANDAN · 2001 to 2015
$4.1MTargeting the cell cycle in triple negative breast cancerR01CA152228 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI KEYOMARSI, KHANDAN · 2011 to 2015
$2.3MNanovectors for Characterization and Destruction of Breast Tumor VasculatureR01CA128797 · NCI · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI FERRARI, MAURO · 2007 to 2010
$1.7MNovel extra cellular RNA-based combinatorial RNA inhibition therapyUH2TR000943 · NCATS · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI CALIN, GEORGE A., LOPEZ-BERESTEIN, GABRIEL · 2013 to 2014
$1.1MNew Reagents for RNA-based Therapeutic TechnologiesR44GM086937 · NIGMS · AM BIOTECHNOLOGIES, LLC · PI YANG, XIANBIN · 2013 to 2014
$997kNCATS NIH HHS UH2 TR000943NCATS NIH HHS UH2 TR000943-01NCI NIH HHS CA016672NCI NIH HHS CA109298NCI NIH HHS CA128797NCI NIH HHS P30 CA016672NCI NIH HHS P50 CA083639NCI NIH HHS P50 CA098258NCI NIH HHS R01 CA087548NCI NIH HHS R01 CA109298NCI NIH HHS R01 CA128797NCI NIH HHS R01 CA152228NCI NIH HHS T32 CA101642NCI NIH HHS U24 CA143835NCI NIH HHS U24CA143835NCI NIH HHS U54 CA151668NIGMS NIH HHS GM084552-04NIGMS NIH HHS GM086937-01NIGMS NIH HHS GM100777-01NIGMS NIH HHS R43 GM084552NIGMS NIH HHS R43 GM086937NIGMS NIH HHS R43 GM100777NIGMS NIH HHS R44 GM084552NIGMS NIH HHS R44 GM086937
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.
Indexed as
AnimalsCell Line, TumorFemaleHumansImmunohistochemistryMiceMice, NudePhosphatesRNA-Induced Silencing ComplexRNA, Small InterferingXenograft Model Antitumor AssaysPhosphatesphosphorodithioic acidRNA-Induced Silencing ComplexRNA, Small Interfering
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