title: Biocompatible gelatin nanoparticles for tumor-targeted delivery of polymerized siRNA in tumor-bearing mice.
abstract: Structural modifications of the siRNA backbone improved its physiochemical properties for incorporating in gene carriers without loss of gene-silencing efficacy. These modifications provide a wider variety of choice of vector systems for siRNA delivery. We developed a tumor-targeted siRNA delivery system using polymerized siRNA (poly-siRNA) and natural polymer gelatin. The polymerized siRNA (poly-siRNA) was prepared through self-polymerization of thiol groups at the 5'-end of sense and anti-sense strands of siRNA and was encapsulated in the self-assembled thiolated gelatin (tGel) nanoparticles (NPs) with chemical cross-linking. The resulting poly-siRNA-tGel (psi-tGel) nanoparticles (average of 145 nm in diameter) protect siRNA molecules from enzymatic degradation, and can be reversibly reduced to release functional siRNA molecules in reductive conditions. The psi-tGel NPs presented efficient siRNA delivery in red fluorescence protein expressing melanoma cells (RFP/B16F10) to down-regulate target gene expression. In addition, the NPs showed low toxicity at a high transfection dose of 125 μg/ml psi-tGel NPs, which included 1 μM of siRNA molecules. In tumor-bearing mice, the psi-tGel NPs showed 2.8 times higher tumor accumulation than the naked poly-siRNA, suggesting tumor-targeted siRNA delivery of psi-tGel NPs. Importantly, the psi-tGel NPs induced effective tumor RFP gene silencing in vivo without remarkable toxicity. The psi-tGel NPs have great potential for a systemic siRNA delivery system for cancer therapy, based on their characteristics of low toxicity, tumor accumulation, and effective siRNA delivery.
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 6, Seongbuk-gu, Seoul 136-791, South Korea.
authors.forename: So Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 6, Seongbuk-gu, Seoul 136-791, South Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Yhee
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 6, Seongbuk-gu, Seoul 136-791, South Korea.
authors.forename: Sun Hwa
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 6, Seongbuk-gu, Seoul 136-791, South Korea; KU-KIST School, Korea University, 1 Anam-dong, Seongbuk-gu, Seoul 136-701, South Korea. Electronic address: ikwon@kist.re.kr.
authors.forename: Ick Chan
authors.initials: IC
authors.lastname: Kwon
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 6, Seongbuk-gu, Seoul 136-791, South Korea. Electronic address: kim@kist.re.kr.
authors.forename: Kwangmeyung
authors.initials: K
authors.lastname: Kim
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005780:Gelatin / Q000737:chemistry*; D015316:Genetic Therapy; D008164:Luminescent Proteins / Q000235:genetics; D008545:Melanoma / Q000235:genetics* / Q000628:therapy; D051379:Mice; D008958:Models, Molecular; D053758:Nanoparticles / Q000737:chemistry*; D058105:Polymerization; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use; D014162:Transfection; D000097573:Red Fluorescent Protein
chemical_list: D005780:Gelatin; D008164:Luminescent Proteins; D034741:RNA, Small Interfering; D000097573:Red Fluorescent Protein
keywords: Gelatin; Nanoparticles; Polymerized siRNA; Tumor-targeted delivery; siRNA delivery system