title: Design and synthesis of novel N-acetylgalactosamine-terminated glycolipids for targeting of lipoproteins to the hepatic asialoglycoprotein receptor.
abstract: A novel glycolipid has been prepared that contains a cluster glycoside with an unusually high affinity for the asialoglycoprotein receptor (ASGPr) and a bile acid moiety that mediates stable incorporation into lipidic particles. The glycolipid spontaneously associated with low-density lipoproteins (LDL) and high-density lipoproteins (HDL) within human and murine plasma, and loading of lipoproteins with this glycolipid resulted in an efficient dose-dependent recognition and uptake of LDL and HDL by the liver (and not by spleen) upon intravenous injection into wild-type mice. Preinjection with asialoorosomucoid largely inhibited the uptake, establishing that both HDL and LDL were selectively recognized and processed by the ASGPr on liver parenchymal cells. Finally, repeated intravenous administration of the glycolipid to hyperlipidemic LDL receptor-deficient mice evoked an efficient and persistent cholesterol-lowering effect. These results indicate that the glycolipid may be a promising alternative for the treatment of hyperlipidemic patients who do not respond sufficiently to current cholesterol-lowering therapies.
authors.affiliation: Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, University of Leiden, Gorlaeus Laboratory, P.O. Box 9502, 2300 RA Leiden, The Netherlands. pcn.rensen@pg.tno.nl
authors.forename: Patrick C N
authors.initials: PC
authors.lastname: Rensen
authors.forename: Steven H
authors.initials: SH
authors.lastname: van Leeuwen
authors.forename: Leo A J M
authors.initials: LA
authors.lastname: Sliedregt
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: van Berkel
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
mesh_terms: D000116:Acetylgalactosamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D037263:Asialoglycoprotein Receptor / Q000187:drug effects* / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D015195:Drug Design; D006017:Glycolipids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy / Q000235:genetics; D007457:Iodine Radioisotopes; D007553:Isotope Labeling; D008075:Lipoproteins, HDL / Q000097:blood / Q000737:chemistry; D008077:Lipoproteins, LDL / Q000097:blood / Q000737:chemistry; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding; D011973:Receptors, LDL / Q000235:genetics
chemical_list: D000924:Anticholesteremic Agents; D037263:Asialoglycoprotein Receptor; D001798:Blood Proteins; D006017:Glycolipids; D007457:Iodine Radioisotopes; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D000116:Acetylgalactosamine