title: Cationic lipid nanoparticles for therapeutic delivery of siRNA and miRNA to murine liver tumor.
abstract: miR-122, a liver-specific tumor suppressor microRNA, is frequently down-regulated in hepatocellular carcinoma (HCC). LNP-DP1, a cationic lipid nanoparticle formulation, was developed as a vehicle to restore deregulated gene expression in HCC cells by miR-122 delivery. LNP-DP1 consists of 2-dioleyloxy-N,N-dimethyl-3-aminopropane (DODMA), egg phosphatidylcholine, cholesterol and cholesterol-polyethylene glycol. In vitro, LNP-DP1-mediated transfection of a miR-122 mimic to HCC cells down-regulated miR-122 target genes by >95%. In vivo, siRNAs/miRNAs encapsulated in LNP-DP1 were preferentially taken up by hepatocytes and tumor cells in a mouse HCC model. The miR-122 mimic in LNP-DP1 was functional in HCC cells without causing systemic toxicity. To demonstrate its therapeutic potential, LNP-DP1 encapsulating miR-122 mimic was intratumorally injected and resulted in ~50% growth suppression of HCC xenografts within 30 days, which correlated well with suppression of target genes and impairment of angiogenesis. These data demonstrate the potential of LNP-DP1-mediated microRNA delivery as a novel strategy for HCC therapy.
  
  
  BACKGROUND
  In this study, LNP-DP1 -a cationic lipid nanoparticle formulation -is reported as a vehicle to restore deregulated gene expression in hepatic carcinoma cells by siRNA and miRNA delivery using a mouse model. Further expansions to this study may enable transition to clinical trials of this system.
authors.affiliation: Molecular, Cellular, and Developmental Biology Program, The Ohio State University, Columbus, OH 43210, USA; Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Shu-Hao
authors.initials: SH
authors.lastname: Hsu
authors.forename: Bo
authors.initials: B
authors.lastname: Yu
authors.forename: Xinmei
authors.initials: X
authors.lastname: Wang
authors.forename: Yuanzhi
authors.initials: Y
authors.lastname: Lu
authors.forename: Carl R
authors.initials: CR
authors.lastname: Schmidt
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lee
authors.forename: L James
authors.initials: LJ
authors.lastname: Lee
authors.forename: Samson T
authors.initials: ST
authors.lastname: Jacob
authors.forename: Kalpana
authors.initials: K
authors.lastname: Ghoshal
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D008958:Models, Molecular; D053758:Nanoparticles / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D014162:Transfection / Q000379:methods
chemical_list: D008055:Lipids; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; C544354:Mirn122 microRNA, mouse; D034741:RNA, Small Interfering
keywords: Cationic lipid nanoparticle; HCC; miR-122; microRNA