title: Iron-Oxide-Based Nanovector for Tumor Targeted siRNA Delivery in an Orthotopic Hepatocellular Carcinoma Xenograft Mouse Model.
abstract: Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide. Small interfering RNA (siRNA) holds promise as a new class of therapeutics for HCC, as it can achieve sequence-specific gene knockdown with low cytotoxicity. However, the main challenge in the clinical application of siRNA lies in the lack of effective delivery approaches that need to be highly specific and thus incur low or no systemic toxicity. Here, a nonviral nanoparticle-based gene carrier is presented that can specifically deliver siRNA to HCC. The nanovector (NP-siRNA-GPC3 Ab) is made of an iron oxide core coated with chitosan-polyethylene glycol (PEG) grafted polyethyleneimine copolymer, which is further functionalized with siRNA and conjugated with a monoclonal antibody (Ab) against human glypican-3 (GPC3) receptor highly expressed in HCC. A rat RH7777 HCC cell line that coexpresses human GPC3 and firefly luciferase (Luc) is established to evaluate the nanovector. The nanoparticle-mediated delivery of siRNA against Luc effectively suppresses Luc expression in vitro without notable cytotoxicity. Significantly, NP-siLuc-GPC3 Ab administered intravenously in an orthotopic model of HCC is able to specifically bound to tumor and induce remarkable inhibition of Luc expression. The findings demonstrate the potential of using this nanovector for targeted delivery of therapeutic siRNA to HCC.
authors.affiliation: Department of Materials Science and Engineering, University of Washington, Seattle, WA, 98195, USA.
authors.forename: Kui
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Neurological Surgery, University of Washington, Seattle, WA, 98195, USA.
authors.forename: Forrest M
authors.initials: FM
authors.lastname: Kievit
authors.affiliation: Department of Surgery, University of Washington, Seattle, WA, 98195, USA.
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Sham
authors.affiliation: Department of Materials Science and Engineering, University of Washington, Seattle, WA, 98195, USA.
authors.forename: Mike
authors.initials: M
authors.lastname: Jeon
authors.affiliation: Department of Materials Science and Engineering, University of Washington, Seattle, WA, 98195, USA.
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Stephen
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.
authors.forename: Arvind
authors.initials: A
authors.lastname: Bakthavatsalam
authors.affiliation: Department of Surgery, University of Washington, Seattle, WA, 98195, USA.
authors.forename: James O
authors.initials: JO
authors.lastname: Park
authors.affiliation: Department of Materials Science and Engineering, University of Washington, Seattle, WA, 98195, USA.|Department of Neurological Surgery, University of Washington, Seattle, WA, 98195, USA.
authors.forename: Miqin
authors.initials: M
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005290:Ferric Compounds / Q000737:chemistry*; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000378:metabolism*; D053673:Glypicans / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D066244:Proton Magnetic Resonance Spectroscopy; D034741:RNA, Small Interfering / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D005290:Ferric Compounds; C105937:GPC3 protein, human; D053673:Glypicans; D034741:RNA, Small Interfering; C000499:ferric oxide; D008156:Luciferases
keywords: RNA interference; copolymer polyethyleneimine; glypican-3; hepatocellular carcinoma; nanoparticles