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N-Linked biantennary and triantennary oligosaccharides containing multiple terminal GalNAc Le(x) (GalNAcss1-4[Fuc-alpha1-3]GlcNAc) determinants were radioiodinated and their pharmacokinetics, biodistribution, and hepatic cellular localization were determined in mice. Pharmacokinetic analysis revealed GalNAc Le(x) biantennary and triantennary oligosaccharides had a similar mean residence time and steady-state volume of distribution but differed in their total body clearance rate due a shorter alpha half-life for GalNAc Le(x) triantennary. Biodistribution and whole-body-autoradiography studies revealed that both GalNAc Le(x) terminated biantennary and triantennary oligosaccharides predominately targeted to the liver, which accumulated 72% and 79% of the dose 30 min after administration, respectively. Separation of mouse liver parenchymal from non-parenchymal cells demonstrated both N-glycans were almost exclusively (94%) taken up by the parenchymal cells. By comparison, GalNAc terminated biantennary and triantennary N-glycans accumulated in the liver with a targeting efficiency of 73% and 81%, respectively. It is concluded that GalNAc and GalNAc Le(x) terminated N-glycans are recognized in vivo with equivalent affinity by the murine hepatic asialoglycoprotein receptor.

Tissue targeting of multivalent GalNAc Lex terminated N-glycans in mice