Preventing acute liver injury via hepatocyte-targeting nano-antioxidants

Abstract

Acute liver injury (ALI) is a severe liver disease that is characterized by sudden and massive hepatocyte necrosis and deterioration of liver functions. Oxidative stress is increasingly recognized as a key factor in the induction and progression of ALI. Scavenging excessive reactive oxygen species (ROS) with antioxidants has become a promising therapeutic option, but intrinsically hepatocyte-targeting antioxidants with excellent bioavailability and biocompatibility are yet to be developed. Herein, self-assembling nanoparticles (NPs) composed of amphiphilic polymers are introduced to encapsulate organic Selenium compound L-Se-methylselenocysteine (SeMC) and form SeMC NPs, which protect the viabilities and functions of cultured hepatocytes in drug- or chemical-induced acute hepatotoxicity models via efficient ROS removal. After further functionalization with the hepatocyte-targeting ligand glycyrrhetinic acid (GA), the resultant GA-SeMC NPs exhibit enhanced hepatocyte uptake and liver accumulation. In mouse models of ALI induced by acetaminophen (APAP) or carbon tetrachloride (CCl₄ ), treatment with GA-SeMC NPs significantly decrease the levels of hepatic lipid peroxidation, tissue vacuolization and serum liver transaminases, while prominently increase that of endogenous antioxidant enzymes. Our study therefore presents a liver-targeting drug delivery strategy for the prevention and treatment of hepatic diseases.