title: Target specific systemic delivery of TGF-β siRNA/(PEI-SS)-g-HA complex for the treatment of liver cirrhosis.
abstract: A target specific systemic delivery system of siRNA therapeutics was successfully developed using reducible polyethyleneimine grafted hyaluronic acid [(PEI-SS)-g-HA] conjugates. The PEI-SS was synthesized by Michael addition of low molecular weight PEI (MW = 2000) with cystaminebisacrylamide (CBA), and grafted to carboxyl groups of HA via amide bond formation after activation with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 1-hydroxybenzotriazole monohydrate (HOBt). The confocal microscopic and fluorometric analyses confirmed the effective cellular uptake of siRNA/(PEI-SS)-g-HA complex by HA receptor mediated endocytosis. In vitro gene silencing efficiency was ca. 80% in the presence of 10 vol% serum and ca. 50% in the presence of 50 vol% serum in B16F1 melanoma cells and activated hepatic stellate cells (HSCs). Furthermore, target specific systemic delivery of apolipoprotein B (ApoB) siRNA/(PEI-SS)-g-HA complex resulted in a drastically reduced ApoB mRNA level down to ca. 20% in a dose-dependent manner. Finally, TGF-β siRNA/(PEI-SS)-g-HA complex showed a feasible therapeutic effect on liver cirrhosis with a significantly reduced nodule formation, collagen content, and HSC number. The siRNA/(PEI-SS)-g-HA complex can be exploited for the target specific systemic treatment of various liver diseases.
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: Sung Woo
authors.initials: SW
authors.lastname: Hong
authors.forename: Wonhee
authors.initials: W
authors.lastname: Hur
authors.forename: Min-Young
authors.initials: MY
authors.lastname: Lee
authors.forename: Jeong-A
authors.initials: JA
authors.lastname: Yang
authors.forename: Sung Woo
authors.initials: SW
authors.lastname: Kim
authors.forename: Seung Kew
authors.initials: SK
authors.lastname: Yoon
authors.forename: Sei Kwang
authors.initials: SK
authors.lastname: Hahn
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D015316:Genetic Therapy / Q000379:methods*; D006820:Hyaluronic Acid / Q000737:chemistry; D008103:Liver Cirrhosis / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D008422:Materials Testing; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D011094:Polyethyleneimine / Q000737:chemistry* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000235:genetics*
chemical_list: D001672:Biocompatible Materials; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; D011094:Polyethyleneimine; D006820:Hyaluronic Acid