Hepatic and Intrahepatic Targeting of Hydrogen Sulfide Prodrug by Bioconjugation.

Hydrogen sulfide (HS) is an endogenous gaseous transmitter known to play an important role in biological functions. For the hepatic and intrahepatic targeting of HS prodrug at the cellular level, we developed two types of sulfo-albumins, in which five sulfide groups (source of HS) were covalently bound to succinylated (Suc) or galactosylated (Gal) bovine serum albumin (BSA). Sulfo-BSA-Suc and polyethylene glycol (PEG)-Sulfo-BSA-Gal, both released HS in the 5 mM glutathione solution, but not in the plasma. Sulfo-BSA-Suc and PEG-Sulfo-BSA-Gal were taken up by RAW264.7 cells (mouse macrophage-like cells) and Hep G2 cells (human hepatocellular carcinoma cells), respectively, and HS was released. These results indicate that Sulfo-BSA-Suc and PEG -Sulfo-BSA-Gal selectively released HS intracellularly. In a biodistribution study, up to 80% of In-labeled Sulfo-BSA-Suc and PEG-Sulfo-BSA-Gal rapidly accumulated in the liver, 30 min after intravenous injection in mice. Furthermore, In-labeled Sulfo-BSA-Suc and PEG-Sulfo-BSA-Gal predominantly accumulated in liver nonparenchymal (endothelial cells and Kupffer cells) and parenchymal cells (hepatocytes), respectively. These findings suggest that targeted delivery of HS prodrug to a specific type of liver cells was successfully achieved by bioconjugation.