title: Development of lipoprotein-like lipid particles for drug targeting: neo-high density lipoproteins.
abstract: The possibility was explored of synthesizing, from commercially available lipids, high density lipoprotein (HDL)-like particles (neo-HDL) with the same physico-chemical and biological properties as native HDL. A preparation method involving egg yolk phosphatidylcholine, cholesterol, and apoproteins from HDL led to the formation of particles with a composition, size, electrophoretic mobility, and density similar to those of discoidal HDL. In vitro experiments with isolated parenchymal liver cells showed that unlabeled HDL and neo-HDL competed for the same high affinity binding sites as did radiolabeled neo-HDL, whereas an excess of unlabeled low density lipoprotein was ineffective. In vivo experiments with radio-labeled neo-HDL indicated that neo-HDL showed a slow decay upon injection into rats, whereas the liver uptake did not exceed > 10% of the injected dose. The small additional liver uptake of radioactivity from neo-HDL, compared with HDL, was due to enhanced uptake by endothelial and Kupffer cells. Lactosylation of neo-HDL led to a markedly increased decay rate and a rapid uptake by rat liver (80% in 10 min). Parenchymal cells accounted for > 90% of the total liver uptake of radiolabeled lactosylated neo-HDL. Because the liver uptake of lactosylated 125I-neo-HDL could be blocked by preinjection of N-acetylgalactosamine, we conclude that the asialoglycoprotein receptor, which is specifically localized on parenchymal liver cells, is responsible for the avid liver uptake. With a fibroblast cell line transfected with the human asialoglycoprotein receptor, it was found that lactosylated neo-HDL binds with high affinity (Kd, 40 nM), in a galactose-specific way. It can be concluded that, with commercially available lipid components, HDL-like particles (neo-HDL) with virtually the same characteristics as found for native apolipoprotein E-free HDL can be reconstituted. Lactosylated neo-HDL, which is rapidly taken up by galactose-specific receptors on parenchymal liver cells, might be used to transport antiviral drugs specifically to parenchymal liver cells.
authors.affiliation: Division of Biopharmaceutics, University of Leiden, The Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: Schouten
authors.forename: M
authors.initials: M
authors.lastname: van der Kooij
authors.forename: J
authors.initials: J
authors.lastname: Muller
authors.forename: M N
authors.initials: MN
authors.lastname: Pieters
authors.forename: M K
authors.initials: MK
authors.lastname: Bijsterbosch
authors.forename: T J
authors.initials: TJ
authors.lastname: van Berkel
mesh_terms: D016475:3T3 Cells; D000116:Acetylgalactosamine / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D002478:Cells, Cultured; D004337:Drug Carriers; D004591:Electrophoresis, Polyacrylamide Gel; D004727:Endothelium / Q000166:cytology / Q000378:metabolism; D007728:Kupffer Cells / Q000166:cytology / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D008075:Lipoproteins, HDL / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: D004337:Drug Carriers; D008055:Lipids; D008075:Lipoproteins, HDL; D000116:Acetylgalactosamine