Stealth lipoplex decorated with triazole-tethered galactosyl moieties: a strong hepatotropic gene vector

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...

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Bibliographic Details
Published in:Biotechnology letters 2015-03, Vol.37 (3), p.567-575
Main Authors: Govender, Dhineshree, Islam, Rafique Ul, De Koning, Charles B, van Otterlo, Willem A. L, Arbuthnot, Patrick, Ariatti, Mario, Singh, Moganavelli
Format: Article
Language:English
Subjects:
Applied Microbiology
Asialoglycoprotein Receptor - agonists
Biochemistry
Biomedical and Life Sciences
Biotechnology
Cell Line
Chemical synthesis
chemistry
cholesterol
copper
Deoxyribonucleic acid
Derivatives
DNA
DNA - metabolism
Embryos
Epithelial Cells - metabolism
ethylene glycol
Gene therapy
Gene Transfer Techniques
Genes
hepatocytes
Hepatocytes - metabolism
human cell lines
Humans
Kidneys
Life Sciences
Ligands
Liposomes - metabolism
Liver cancer
Mathematical analysis
Microbiology
Original Research Paper
Polyethylene glycol
transfection
Vectors (mathematics)
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Summary: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.
ISSN:0141-5492
1573-6776
DOI:10.1007/s10529-014-1729-5