Multivalent Targeting of the Asialoglycoprotein Receptor by Virus-Like Particles

Area of Science:

• Hepatology
• Nanomedicine
• Cellular Biology

Background:

• The asialoglycoprotein receptor (ASGPR) is highly expressed on hepatocytes, offering a target for liver-specific drug delivery.
• Multivalent galactosylated carbohydrates bind ASGPR, facilitating the hepatic delivery of conjugated molecules.

Purpose of the Study:

• To develop and evaluate virus-like particle (VLP) conjugates for efficient ASGPR-mediated hepatic delivery.
• To investigate the impact of ligand density and affinity on VLP cellular uptake and liver targeting.

Main Methods:

• Conjugation of high-affinity galactosylated ligands to VLPs.
• In vitro assessment of VLP endocytosis by ASGPR-expressing HepG2 cells.
• In vivo biodistribution studies of targeted and non-targeted VLPs in mice.

Main Results:

• Optimized VLP-ligand conjugates demonstrated efficient ASGPR-dependent endocytosis, outperforming small molecules and natural ligands.
• In vivo studies showed rapid liver clearance and association with various liver cell types, including hepatocytes, Kupffer cells, and sinusoidal endothelial cells.
• While ASGPR-targeted VLPs showed increased hepatocyte association compared to non-targeted ones, significant uptake by non-parenchymal cells limited selective targeting.

Conclusions:

• ASGPR-targeted VLPs represent a promising platform for hepatic delivery, with uptake efficiency dependent on ligand characteristics.
• Despite potent ASGPR targeting, achieving exclusive hepatocyte delivery is challenging due to substantial uptake by Kupffer cells and endothelial cells.
• Selective cellular trafficking within the liver remains a significant hurdle, even with optimized targeting strategies.