1. Multivalent Targeting of the Asialoglycoprotein Receptor by Virus-Like Particles.
- Author
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Hincapie R, Bhattacharya S, Baksh MM, Sanhueza CA, Echeverri ES, Kim H, Paunovska K, Podilapu AR, Xu M, Dahlman JE, and Finn MG
- Subjects
- Animals, Mice, Asialoglycoprotein Receptor, Ligands, Hepatocytes metabolism, Endothelial Cells metabolism, Liver metabolism
- Abstract
The asialoglycoprotein receptor (ASGPR) is expressed in high density on hepatocytes. Multivalent variants of galactosyl carbohydrates bind ASGPR with high affinity, enabling hepatic delivery of ligand-bound cargo. Virus-like particle (VLP) conjugates of a relatively high-affinity ligand were efficiently endocytosed by ASGPR-expressing cells in a manner strongly dependent on the nature and density of ligand display, with the best formulation using a nanomolar-, but not a picomolar-level, binder. Optimized particles were taken up by HepG2 cells with greater efficiency than competing small molecules or the natural multigalactosylated ligand, asialoorosomucoid. Upon systemic injection in mice, these VLPs were rapidly cleared to the liver and were found in association with sinusoidal endothelial cells, Kupffer cells, hepatocytes, dendritic cells, and other immune cells. Both ASGPR-targeted and nontargeted particles were distributed similarly to endothelial and Kupffer cells, but targeted particles were distributed to a greater number and fraction of hepatocytes. Thus, selective cellular trafficking in the liver is difficult to achieve: even with the most potent ASGPR targeting available, barrier cells take up much of the injected particles and hepatocytes are accessed only approximately twice as efficiently in the best case., (© 2023 Wiley-VCH GmbH.)
- Published
- 2023
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