title: Target specific tumor treatment by VEGF siRNA complexed with reducible polyethyleneimine-hyaluronic acid conjugate.
abstract: Target specific delivery of small interfering RNA (siRNA) has been regarded as one of the most important technologies for the development of siRNA therapeutics. In this work, non-toxic low molecular weight (MW) polyethyleneimine (PEI, 2000 Da) was cross-linked with cystamine bisacrylamide (CBA) to prepare reducible PEI-SS in the body. Then, PEI-SS was conjugated with hyaluronic acid (HA) in the form of block-copolymer to enhance serum stability and facilitate target specific cellular uptake of siRNA by HA receptor mediated endocytosis. The cytotoxicity of (PEI-SS)-b-HA conjugate appeared to be negligible likely due to the degradation of PEI-SS to low MW PEI in the cytosol. Flow cytometric and confocal microscopic analyses confirmed the HA receptor mediated endocytosis of siRNA/(PEI-SS)-b-HA complex. The siRNA/(PEI-SS)-b-HA complex demonstrated an excellent in vitro gene silencing efficiency in the range of 50-80% reducing the mRNA expression level in the absence and presence of 50 vol% serum. Moreover, intra-tumoral injection of vascular endothelial growth factor (VEGF) siRNA/(PEI-SS)-b-HA complex resulted in dramatically inhibited tumor growth with reduced VEGF mRNA and VEGF levels in the tumors.
authors.affiliation: School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology , San 31, Hyoja-dong, Nam-gu, Pohang, Kyungbuk 790-784, Republic of Korea.
authors.forename: Kitae
authors.initials: K
authors.lastname: Park
authors.forename: Min-Young
authors.initials: MY
authors.lastname: Lee
authors.forename: Ki Su
authors.initials: KS
authors.lastname: Kim
authors.forename: Sei Kwang
authors.initials: SK
authors.lastname: Hahn
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006820:Hyaluronic Acid / Q000737:chemistry*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D011094:Polyethyleneimine / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics*; D014162:Transfection / Q000379:methods*; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics
chemical_list: D004337:Drug Carriers; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D011094:Polyethyleneimine; D006820:Hyaluronic Acid