Rationally Designed Galactose Dendrimer for Hepatocyte-Specific Targeting and Intracellular Drug Delivery for the Treatment of Liver Disorders.

Over two million people die of liver disorders every year globally. Hepatocytes are the key cells affected in several acute and chronic liver diseases. The current clinical outcomes of liver-targeted nanoparticles are limited, necessitating the need to develop smart hepatocyte-targeted drug delivery systems. Here, we present the rational design and development of a hepatocyte-targeting glycodendrimer (GAL-24) built from biocompatible building blocks, using expedite and facile chemical methodology. GAL-24 is designed to inherently target asialoglycoprotein receptor 1 (ASGP-R) on hepatocytes and shows significant accumulation in the liver (20% of injected dose), just 1 h after systemic administration. This is highly specific to hepatocytes, with over 80% of hepatocytes showing GAL-24-Cy5 signal at 24 h. GAL-24-Cy5 maintains hepatocyte-targeting capabilities in both a mouse model of severe acetaminophen poisoning-induced hepatic necrosis and a rat model of nonalcoholic steatohepatitis (NASH). This GAL-24 nanoplatform holds great promise for improved drug delivery to hepatocytes to combat many liver disorders.