title: Stealth lipoplex decorated with triazole-tethered galactosyl moieties: a strong hepatotropic gene vector.
abstract: Mono-antennary galacto derivatives of cholesterol are being actively developed to direct lipoplexes to the asialoglycoprotein receptor (ASGP-R) on hepatocytes. Here we report on a novel ASGP-R ligand cholest-5-en-3-yl [1-(β-D-galactopyranosyl)-1H-1,2,3-triazol-4-yl]methylcarbamate (4), assembled by a copper(I)-catalyzed azide-alkyne cycloaddition (click chemistry), and compare it with cholest-5-en-3-yl-β-D-galactopyranoside (2) and cholest-5-en-3-yl [1-(β-D-galactopyranosyl-1'-oxy)phen-4-yl]carbamate (3), in liposome formulations with or without 5 mol% distearoylphosphatidylethanolamine poly(ethylene glycol)2000, intended for DNA delivery to ASGP-R-positive hepatocyte-derived HepG2 cells and the ASGP-R-negative embryo kidney cell line HEK293. Transfection levels attained with lipoplex 4 were 100 and 300% greater than those for lipoplexes 2 and 3 respectively in HepG2 cells, while competition assays reduced transfection levels by up to 98%. Transfection activities achieved in HEK293 cells were up to three orders of magnitude lower. Therefore, 4 is representative of a new class of promising hepatotropic ligands for gene delivery.
authors.affiliation: Non-viral Gene Delivery Laboratory, Discipline of Biochemistry, University of KwaZulu-Natal, Durban, South Africa, Dhineshree.Govender@caprisa.org.
authors.forename: Dhineshree
authors.initials: D
authors.lastname: Govender
authors.forename: Rafique Ul
authors.initials: RU
authors.lastname: Islam
authors.forename: Charles B
authors.initials: CB
authors.lastname: De Koning
authors.forename: Willem A L
authors.initials: WA
authors.lastname: van Otterlo
authors.forename: Patrick
authors.initials: P
authors.lastname: Arbuthnot
authors.forename: Mario
authors.initials: M
authors.lastname: Ariatti
authors.forename: Moganavelli
authors.initials: M
authors.lastname: Singh
mesh_terms: D037263:Asialoglycoprotein Receptor / Q000819:agonists*; D002460:Cell Line; D004247:DNA / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D018014:Gene Transfer Techniques; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008081:Liposomes / Q000378:metabolism*
chemical_list: D037263:Asialoglycoprotein Receptor; D008081:Liposomes; D004247:DNA