title: Mesoporous silica nanoparticle delivery of chemically modified siRNA against TWIST1 leads to reduced tumor burden.
abstract: Growth and progression of solid tumors depend on the integration of multiple pro-growth and survival signals, including the induction of angiogenesis. TWIST1 is a transcription factor whose reactivation in tumors leads to epithelial to mesenchymal transition (EMT), including increased cancer cell stemness, survival, and invasiveness. Additionally, TWIST1 drives angiogenesis via activation of IL-8 and CCL2, independent of VEGF signaling. In this work, results suggest that chemically modified siRNA against TWIST1 reverses EMT both in vitro and in vivo. siRNA delivery with a polyethyleneimine-coated mesoporous silica nanoparticle (MSN) led to reduction of TWIST1 target genes and migratory potential in vitro. In mice bearing xenograft tumors, weekly intravenous injections of the siRNA-nanoparticle complexes resulted in decreased tumor burden together with a loss of CCL2 suggesting a possible anti-angiogenic response. Therapeutic use of TWIST1 siRNA delivered via MSNs has the potential to inhibit tumor growth and progression in many solid tumor types.
  
  
  BACKGROUND
  Tumor progression and metastasis eventually lead to patient mortality in the clinical setting. In other studies, it has been found that TWIST1, a transcription factor, if reactivated in tumors, would lead to downstream events including angiogenesis and result in poor prognosis in cancer patients. In this article, the authors were able to show that when siRNA against TWIST1 was delivered via mesoporous silica nanoparticle, there was tumor reduction in an in-vivo model. The results have opened up a new avenue for further research in this field.
authors.affiliation: Division of Comparative Medicine and, Irell & Manella Graduate School of Biological Sciences, City of Hope, Beckman Research Institute, Duarte, CA, USA. Electronic address: jfinlay@coh.org.
authors.forename: James
authors.initials: J
authors.lastname: Finlay
authors.affiliation: Irell & Manella Graduate School of Biological Sciences, City of Hope, Beckman Research Institute, Duarte, CA, USA. Electronic address: croberts@coh.org.
authors.forename: Cai M
authors.initials: CM
authors.lastname: Roberts
authors.affiliation: Department of Chemistry and Biochemistry, Jonsson Comprehensive Cancer Center, California NanoSystems Institute, University of California Los Angeles, Los Angeles, CA, USA. Electronic address: jdong@chem.ucla.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, CA, 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, CA, USA. Electronic address: fuyut@microbio.ucla.edu.
authors.forename: Fuyuhiko
authors.initials: F
authors.lastname: Tamanoi
authors.affiliation: Department of Neurosciences, City of Hope, Beckman Research Institute, Duarte, CA, USA. Electronic address: cglackin@coh.org.
authors.forename: Carlotta A
authors.initials: CA
authors.lastname: Glackin
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018014:Gene Transfer Techniques; D006801:Humans; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009369:Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000628:therapy*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry; D012822:Silicon Dioxide / Q000008:administration & dosage / Q000737:chemistry; D047368:Tumor Burden / Q000235:genetics; D051879:Twist-Related Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D012822:Silicon Dioxide
keywords: Angiogenesis; Mesoporous silica; TWIST1; siRNA