Trivalent, Gal/GalNAc-containing ligands designed for the asialoglycoprotein receptor.
A series of novel, fluorescent ligands designed to bind with high affinity and specificity to the asialoglycoprotein receptor (ASGP-R) has been synthesized and tested on human liver cells. The compounds bear three non-reducing, beta-linked Gal or GalNAc moieties linked to flexible spacers for an optimal spatial interaction with the binding site of the ASGP-R. The final constructs were selectively endocytosed by HepG2 cells derived from parenchymal liver cells-the major human liver cell type-in a process that was visualized with the aid of fluorescence microscopy. Furthermore, the internalization was analyzed with flow cytometry, which showed the process to be receptor-mediated and selective. The compounds described in this work could serve as valuable tools for studying hepatic endocytosis, and are suited as carriers for site-specific drug delivery to the liver.
Khorev
Oleg
O
Institute of Molecular Pharmacy, Pharmacenter-University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
Stokmaier
Daniela
D
Schwardt
Oliver
O
Cutting
Brian
B
Ernst
Beat
B
D015295:Antigens, Tumor-Associated, Carbohydrate / Q000737:chemistry*; D037263:Asialoglycoprotein Receptor / Q000737:chemistry / Q000187:drug effects*; D001665:Binding Sites; D045744:Cell Line, Tumor; D015195:Drug Design; D005434:Flow Cytometry / Q000379:methods; D005453:Fluorescence; D006801:Humans; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008856:Microscopy, Fluorescence / Q000379:methods; D015394:Molecular Structure; D011409:Propylene Glycols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D015295:Antigens, Tumor-Associated, Carbohydrate; D037263:Asialoglycoprotein Receptor; D008024:Ligands; D011409:Propylene Glycols; C016467:Thomsen-Friedenreich antigen