title: Targeted delivery of plasmid DNA complexed with galactosylated poly(L-lysine).
abstract: Galactose was introduced to poly(L-lysine) (PLL) with an average molecular weight of 13,000 to develop a hepatocyte-specific carrier for gene drugs. The pharmacokinetic characteristics of a model plasmid, pCAT (plasmid DNA encoding chloramphenicol acetyltransferase reporter gene), complexed with galactosylated PLL (Gal-PLL) was studied in mice in relation to its physicochemical properties. pCAT/Gal-PLL complex at a ratio of 1:0.6 (w/w) has a zeta potential of -20 mV and a mean particle size of about 180 nm. After intravenous injection, [32P]pCAT/Gal-PLL was rapidly eliminated from the circulation and preferentially taken up by the liver's parenchymal cells. The hepatic uptake of [32P]pCAT/Gal-PLL was significantly inhibited by prior administration of Gal-bovine serum albumin, suggesting that the uptake was mediated by the asialoglycoprotein receptors on hepatocytes. In vitro transfection experiments using a hepatoma cell line expressing the asialoglycoprotein receptor revealed that pCAT/Gal-PLL gave a high CAT gene expression whereas pCAT complexed with unmodified PLL failed to transfect the cells.
authors.affiliation: Department of Drug Delivery Research, Faculty of Pharmaceutical Sciences, Kyoto University, Japan. hashidam@pharm.kyoto-u.ac.jp
authors.forename: M
authors.initials: M
authors.lastname: Hashida
authors.forename: S
authors.initials: S
authors.lastname: Takemura
authors.forename: M
authors.initials: M
authors.lastname: Nishikawa
authors.forename: Y
authors.initials: Y
authors.lastname: Takakura
mesh_terms: D000818:Animals; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D004247:DNA / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D004337:Drug Carriers; D005690:Galactose / Q000737:chemistry; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D010316:Particle Size; D010957:Plasmids; D011107:Polylysine / Q000737:chemistry*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D004337:Drug Carriers; D011107:Polylysine; D004247:DNA; D015500:Chloramphenicol O-Acetyltransferase; D005690:Galactose