A new N-acetylgalactosamine containing peptide as a targeting vehicle for mammalian hepatocytes via asialoglycoprotein receptor endocytosis

Galactoside-containing cluster ligands have high affinity for asialoglycoprotein receptors (ASGP-r), which are found in abundance in mammalian parenchymal liver cells. These ligands may be conjugated with a therapeutic drug to improve the efficiency of delivery to diseased liver cells. This report d...

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Bibliographic Details
Published inCurrent drug delivery Vol. 1; no. 2; p. 119
Main Authors Wu, Ying-Ta, Jiaang, Weir-Torn, Lin, Kuo-Ging, Huang, Chun-Ming, Chang, Chin-Hsien, Sun, Ying-Ling, Fan, Kuo-Hsien, Hsu, Wei-Chuan, Wang, Hsin-Ell, Lin, Shwu-Bin, Chen, Shui-Tein
Format Journal Article
LanguageEnglish
Published United Arab Emirates 01.04.2004
Subjects
Acetylgalactosamine - chemistry
Animals
Asialoglycoprotein Receptor - metabolism
Cell Line, Tumor
Chemistry, Pharmaceutical
Drug Carriers
Endocytosis
Glycopeptides - chemical synthesis
Glycopeptides - pharmacokinetics
Glycopeptides - pharmacology
Hepatocytes - drug effects
Hepatocytes - metabolism
Humans
Kidney - metabolism
Ligands
Mice
Mice, Inbred BALB C
Rats
Rats, Inbred F344
Tissue Distribution
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Summary:Galactoside-containing cluster ligands have high affinity for asialoglycoprotein receptors (ASGP-r), which are found in abundance in mammalian parenchymal liver cells. These ligands may be conjugated with a therapeutic drug to improve the efficiency of delivery to diseased liver cells. This report describes a new synthetic route towards clustering glycopeptides containing N-acetyl-D-galactosamine (GalNAc). The building block Fmoc-alpha-(ah-Ac3GalNAc)-L-glutamate allowed access to the target compound YEEE(alpha-ah-GalNAc)(3), a structural mimic of YEE(ah-GalNAc)(3), via solid phase peptide synthesis (SPPS). Fatty acid, poly-lysine, fluorescein and biotin conjugates further demonstrate the facility of the described method. Using fluorescein labeling and 131I labeling, in vitro and in vivo assays confirmed that YEEE(alpha-ah-GalNAc)(3) possesses both specificity and affinity to the liver, similar to the agent YEE(ah-GalNAc)(3), which targets liver lesions. The synthesis described in this report represents a considerable improvement in synthesizing a ligand for ASGP-r by simplifying both the preparation of the starting material and the procedure for conjugating the galactosidase cluster to drugs.
ISSN:1567-2018
DOI:10.2174/1567201043479939