title: Synthesis of galactosyl compounds for targeted gene delivery.
abstract: Cell-specific DNA delivery offers a great potential for targeted gene therapy. Toward this end, we have synthesized a series of compounds carrying galactose residues as a targeting ligand for asialoglycoprotein receptors of hepatocytes and primary amine groups as a functional domain for DNA binding. Biological activity of these galactosyl compounds in DNA delivery was evaluated in HepG2 and BL-6 cells and compared with respect to the number of galactose residues as well as primary amine groups in each molecule. Transfection experiments using a firefly luciferase gene as a reporter revealed that compounds with multivalent binding properties were more active in DNA delivery. An optimal transfection activity in HepG2 cells requires seven primary amine groups and a minimum of two galactose residues in each molecule. The transfection activity of compounds carrying multi-galactose residues can be inhibited by asialofetuin, a natural substrate for asialoglycoprotein receptors of hepatocytes, suggesting that gene transfer by these galactosyl compounds is asialoglycoprotein receptor-mediated. These results provide direct evidence in support of our new strategy for the use of small and synthetic compounds for cell specific and targeted gene delivery.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: T
authors.initials: T
authors.lastname: Ren
authors.forename: G
authors.initials: G
authors.lastname: Zhang
authors.forename: D
authors.initials: D
authors.lastname: Liu
mesh_terms: D000818:Animals; D001212:Asialoglycoproteins / Q000494:pharmacology; D004247:DNA / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems / Q000379:methods*; D060748:Fetuins; D005690:Galactose / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D017930:Genes, Reporter; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008156:Luciferases / Q000235:genetics; D051379:Mice; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism*; D010980:Platelet Membrane Glycoproteins; D013329:Structure-Activity Relationship; D013501:Surface-Active Agents / Q000737:chemistry / Q000493:pharmacokinetics; D014162:Transfection / Q000379:methods* / Q000592:standards; D014407:Tumor Cells, Cultured / Q000378:metabolism; D000509:alpha-Fetoproteins / Q000494:pharmacology
chemical_list: D001212:Asialoglycoproteins; D060748:Fetuins; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins; D013501:Surface-Active Agents; D000509:alpha-Fetoproteins; C017029:asialofetuin; C032193:glycoprotein receptor GPIb-IX; D004247:DNA; D008156:Luciferases; D005690:Galactose