title: In vivo targeting function of N-linked oligosaccharides with terminating galactose and N-acetylgalactosamine residues.
abstract: N-Linked biantennary, triantennary, and core fucosylated biantennary oligosaccharides were isolated from animal glycoproteins and derivatized at their reducing end with Boc-tyrosine. The terminal Gal residues were enzymatically removed and replaced with GalNAc. Tyrosinamide-oligosaccharides were radioiodinated and administered intravenously to mice. Pharmacokinetic and biodistribution studies revealed structure-dependent differences in the steady-state volume of distribution, total body clearance rate, and targeting efficiency. Tyrosinamide-oligosaccharides were found to resist metabolism relative to a natural triantennary glycopeptide which was rapidly degraded in vivo. Triantennary oligosaccharides containing terminal Gal or Gal-NAc targeted the liver efficiently whereas biantennary oligosaccharides containing terminal Gal residues and differing only in their core fucosylation avoided recognition by the asialoglycoprotein receptor and were cleared unmetabolized by renal filtration. In contrast, biantennary oligosaccharides containing terminal Gal-NAc residues targeted the liver with much greater efficiency than Gal-terminated triantennary oligosaccharide. Core fucosylation reduced the metabolism rate of tyrosinamide-biantennary in the liver. The results establish the utility of tyrosinamide-oligosaccharides as probes to analyze the ligand specificity of mammalian lectins in vivo and demonstrate that a GalNAc-terminated biantennary is a potent ligand for the asialoglycoprotein receptor.
authors.affiliation: Division of Pharmaceutics and Pharmaceutical Chemistry, Ohio State University, Columbus 43210.
authors.forename: M H
authors.initials: MH
authors.lastname: Chiu
authors.forename: T
authors.initials: T
authors.lastname: Tamura
authors.forename: M S
authors.initials: MS
authors.lastname: Wadhwa
authors.forename: K G
authors.initials: KG
authors.lastname: Rice
mesh_terms: D000116:Acetylgalactosamine / Q000737:chemistry*; D000818:Animals; D037263:Asialoglycoprotein Receptor; D001692:Biological Transport; D002240:Carbohydrate Sequence; D005690:Galactose / Q000737:chemistry*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008657:Metabolic Clearance Rate; D051379:Mice; D008813:Mice, Inbred ICR; D008969:Molecular Sequence Data; D009844:Oligosaccharides / Q000737:chemistry* / Q000493:pharmacokinetics*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D016339:Spectrometry, Mass, Fast Atom Bombardment; D014018:Tissue Distribution; D014443:Tyrosine / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D037263:Asialoglycoprotein Receptor; D008024:Ligands; D009844:Oligosaccharides; D011956:Receptors, Cell Surface; C036387:tyrosinamide; D014443:Tyrosine; D000116:Acetylgalactosamine; D005690:Galactose