title: Nanoparticle delivery of siRNA against TWIST to reduce drug resistance and tumor growth in ovarian cancer models.
abstract: Epithelial ovarian cancer (EOC) is the most deadly gynecologic malignancy on account of its late stage at diagnosis and frequency of drug resistant recurrences. Novel therapies to overcome these barriers are urgently needed. TWIST is a developmental transcription factor reactivated in cancers and linked to angiogenesis, metastasis, cancer stem cell phenotype, and drug resistance, making it a promising therapeutic target. In this work, we demonstrate the efficacy of TWIST siRNA (siTWIST) and two nanoparticle delivery platforms to reverse chemoresistance in EOC models. Polyamidoamine dendrimers and mesoporous silica nanoparticles (MSNs) carried siTWIST into target cells and led to sustained TWIST knockdown in vitro. Mice treated with cisplatin plus MSN-siTWIST exhibited lower tumor burden than mice treated with cisplatin alone, with most of the effect coming from reduction in disseminated tumors. This platform has potential application for overcoming the clinical challenges of metastasis and chemoresistance in EOC and other TWIST overexpressing cancers.
authors.affiliation: Irell & Manella Graduate School of Biological Sciences, City of Hope-Beckman Research Institute, Duarte, California, USA; Department of Stem Cell and Developmental Biology, City of Hope-Beckman Research Institute Duarte, California, USA. Electronic address: cai.roberts@yale.edu.
authors.forename: Cai M
authors.initials: CM
authors.lastname: Roberts
authors.affiliation: Irell & Manella Graduate School of Biological Sciences, City of Hope-Beckman Research Institute, Duarte, California, USA; Department of Stem Cell and Developmental Biology, City of Hope-Beckman Research Institute Duarte, California, USA. Electronic address: sshahin@coh.org.
authors.forename: Sophia Allaf
authors.initials: SA
authors.lastname: Shahin
authors.affiliation: Department of Chemistry and Biochemistry, Jonsson Comprehensive Cancer Center, California NanoSystems Institute, University of California Los Angeles, Los Angeles, California, USA. Electronic address: wwen@coh.org.
authors.forename: Wei
authors.initials: W
authors.lastname: Wen
authors.affiliation: Irell & Manella Graduate School of Biological Sciences, City of Hope-Beckman Research Institute, Duarte, California, USA; Department of Stem Cell and Developmental Biology, City of Hope-Beckman Research Institute Duarte, California, USA. Electronic address: jamesfinlay@gmail.com.
authors.forename: James B
authors.initials: JB
authors.lastname: Finlay
authors.affiliation: Department of Chemistry and Biochemistry, Jonsson Comprehensive Cancer Center, California NanoSystems Institute, University of California Los Angeles, Los Angeles, California, USA. Electronic address: juyao@mit.edu.
authors.forename: Juyao
authors.initials: J
authors.lastname: Dong
authors.affiliation: Department of Chemistry and Biochemistry, Jonsson Comprehensive Cancer Center, California NanoSystems Institute, University of California Los Angeles, Los Angeles, California, USA. Electronic address: wangrn8600@gmail.com.
authors.forename: Ruining
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Surgery, City of Hope-Beckman Research Institute, California, USA. Electronic address: tdellinger@coh.org.
authors.forename: Thanh H
authors.initials: TH
authors.lastname: Dellinger
authors.affiliation: Department of Chemistry and Biochemistry, Jonsson Comprehensive Cancer Center, California NanoSystems Institute, University of California Los Angeles, Los Angeles, California, USA. Electronic address: zink@chem.ucla.edu.
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Zink
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, Jonsson Comprehensive Cancer Center, California NanoSystems Institute, University of California Los Angeles, Los Angeles, California, USA. Electronic address: fuyut@microbio.ucla.edu.
authors.forename: Fuyuhiko
authors.initials: F
authors.lastname: Tamanoi
authors.affiliation: Department of Stem Cell and Developmental Biology, City of Hope-Beckman Research Institute Duarte, California, USA. Electronic address: cglackin@coh.org.
authors.forename: Carlotta A
authors.initials: CA
authors.lastname: Glackin
mesh_terms: D000818:Animals; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D050091:Dendrimers / Q000737:chemistry; D005260:Female; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D010053:Ovary / Q000378:metabolism / Q000473:pathology; D016062:Porosity; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use*; D000067492:RNAi Therapeutics / Q000379:methods*; D012822:Silicon Dioxide / Q000737:chemistry*; D051879:Twist-Related Protein 1 / Q000235:genetics*
chemical_list: D050091:Dendrimers; C104700:PAMAM Starburst; D034741:RNA, Small Interfering; D051879:Twist-Related Protein 1; D012822:Silicon Dioxide
keywords: Mesoporous silica nanoparticles; Ovarian cancer; Polyamidoamine dendrimers; Twist; siRNA