title: Formulation of glutathione responsive anti-proliferative nanoparticles from thiolated Akt1 siRNA and disulfide-crosslinked PEI for efficient anti-cancer gene therapy.
abstract: In this study, thiol-modified siRNA (SH-siRNA) was delivered by bioreducible polyethylenimine (ssPEI), to enhance physicochemical properties of polyplexes and function of siRNA through disulfide bonding between SH-siRNA and ssPEI. The ssPEI was utilized to deliver Akt1 SH-siRNA for suppression of Akt1 mRNA and blockage of Akt1 protein translation, resulting in reduced cellular proliferation and the induction of apoptosis. Disulfide bondings between the ssPEI and SH-siRNA through thiol groups in both were confirmed by DTT treatment. Complexation between ssPEI and Akt1SH-siRNA was enhanced and reduced surface charge of ssPEI/Akt1SH-siRNA complexes with smaller average particle sizes even at lower N/P ratios was obtained compared with PEI/Akt1siRNA ones. Cellular uptake of ssPEI/Akt1SH-siRNA complexes in CT-26 mouse colon cancer cells was also enhanced. The ssPEI/Akt1SH-siRNA complexes reduced proliferation and increased apoptosis of mouse colon cancer cells in vitro. In an in vivo mouse tumor model, the complexes reduced tumor proliferation and downregulation of Akt1 compared to controls.
authors.affiliation: Department of Biomedical Sciences, BK21 PLUS Center for Creative Biomedical Scientists at Chonnam National University, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-757, South Korea.
authors.forename: Muthunarayanan
authors.initials: M
authors.lastname: Muthiah
authors.affiliation: Department of Biomedical Sciences, BK21 PLUS Center for Creative Biomedical Scientists at Chonnam National University, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-757, South Korea.
authors.forename: Hui-Lian
authors.initials: HL
authors.lastname: Che
authors.affiliation: Department of Biomedical Sciences, BK21 PLUS Center for Creative Biomedical Scientists at Chonnam National University, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-757, South Korea.
authors.forename: Santhosh
authors.initials: S
authors.lastname: Kalash
authors.affiliation: Department of Biomedical Sciences, BK21 PLUS Center for Creative Biomedical Scientists at Chonnam National University, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-757, South Korea.
authors.forename: Jihoon
authors.initials: J
authors.lastname: Jo
authors.affiliation: Department of Biomedical Sciences, BK21 PLUS Center for Creative Biomedical Scientists at Chonnam National University, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-757, South Korea.
authors.forename: Seok-Yong
authors.initials: SY
authors.lastname: Choi
authors.affiliation: Department of Chemistry, Pohang University of Science and Technology, Pohang 790-784, South Korea.
authors.forename: Won Jong
authors.initials: WJ
authors.lastname: Kim
authors.affiliation: Department of Agricultural Biotechnology, Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, South Korea.
authors.forename: Chong Su
authors.initials: CS
authors.lastname: Cho
authors.affiliation: School of Materials Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 500-712, South Korea.
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Biomedical Sciences, BK21 PLUS Center for Creative Biomedical Scientists at Chonnam National University, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-757, South Korea. Electronic address: pik96@chonnam.ac.kr.
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Park
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy; D003432:Cross-Linking Reagents / Q000737:chemistry; D004195:Disease Models, Animal; D004220:Disulfides / Q000737:chemistry*; D015316:Genetic Therapy; D005978:Glutathione / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry*; D011094:Polyethyleneimine / Q000138:chemical synthesis / Q000737:chemistry*; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics*; D034741:RNA, Small Interfering / Q000737:chemistry* / Q000235:genetics / Q000627:therapeutic use; D013438:Sulfhydryl Compounds / Q000737:chemistry
chemical_list: D003432:Cross-Linking Reagents; D004220:Disulfides; D034741:RNA, Small Interfering; D013438:Sulfhydryl Compounds; D011094:Polyethyleneimine; D051057:Proto-Oncogene Proteins c-akt; D005978:Glutathione
keywords: Akt1; Bioreducible PEI; Colon cancer; Thiol modification; Tumor suppression; siRNA