DEVELOPMENT OF LIPOPROTEIN-LIKE LIPID PARTICLES FOR DRUG TARGETING - NEO-HIGH DENSITY LIPOPROTEINS

The possibility was explored of synthesizing, from commercially availa ble lipids, high density lipoprotein (HDL)-like particles (neo-HDL) wi th the same physico-chemical and biological properties as native HDL. A preparation method involving egg yolk phosphatidylcholine, cholester ol, and apoproteins from HDL led to the formation of particles with a composition, size, electrophoretic mobility, and density similar to th ose of discoidal HDL. In vitro experiments with isolated parenchymal l iver cells showed that unlabeled HDL and neo-HDL competed for the same high affinity binding sites as did radiolabeled neo-HDL, whereas an e xcess of unlabeled low density lipoprotein was ineffective. In vivo ex periments with radio-labeled neo-HDL indicated that neo-HDL showed a s low decay upon injection into rats, whereas the liver uptake did not e xceed >10% of the injected dose. The small additional liver uptake of radioactivity from neo-HDL, compared with HDL, was due to enhanced upt ake by endothelial and Kupffer cells. Lactosylation of neo-HDL led to a markedly increased decay rate and a rapid uptake by rat liver (80% i n 10 min). Parenchymal cells accounted for >90% of the total liver upt ake of radiolabeled lactosylated neo-HDL. Because the liver uptake of lactosylated I-125-neo-HDL could be blocked by preinjection of NS-acet ylgalactosamine, we conclude that the asialoglycoprotein receptor, whi ch is specifically localized on parenchymal liver cells, is responsibl e for the avid liver uptake. With a fibroblast cell line transfected w ith the human asialoglycoprotein receptor, it was found that lactosyla ted neo-HDL binds with high affinity (K(d), 40 nm), in a galactose-spe cific way. It can be concluded that, with commercially available lipid components, HDL-like particles (neo-HDL) with virtually the same char acteristics as found for native apolipoprotein E-free HDL can be recon stituted. Lactosylated neo-HDL, which is rapidly taken up by galactose -specific receptors on parenchymal liver cells, might be used to trans port antiviral drugs specifically to parenchymal liver cells.