Polythiol-containing, recombinant mannosylated-albumin is a superior CD68+/CD206+ Kupffer cell-targeted nano-antioxidant for the treatment of two acute hepatitis models

Abstract

Since reactive oxygen species (ROS) derived from Kupffer cells (KC), especially CD68+ KC, play a key role in the induction of hepatic oxidative stress and injuries, we newly developed a polythiolated- and mannosylated-human serum albumin (SH-Man-HSA), a novel nano-antioxidant for delivering thiol to CD68+ KC. In vitro electron paramagnetic resonance (EPR) coupled with an in vivo pharmacokinetic and immunohistochemical study showed that SH-Man-HSA possessed powerful radical scavenging activity and was rapidly and selectively delivered thiols to the liver via mannose receptor (CD206) presented on the CD68+ cells surface. SH-Man-HSA significantly improved the survival rate of concanavalin-A (Con-A) treated mice. Moreover, SH-Man-HSA exhibited excellent hepato-protective action, not by influencing TNF or IFN-? production that closely associated with Con-A induced hepatitis, but by suppressing ROS production. Interestingly, such protective effect of SH-Man-HSA was superior to N-acetylcysteine (NAC). This could be due to the difference in the inhibition of hepatic oxidative stress between two antioxidant depending upon their potential of thiol delivery to liver. Similar results were also observed for acetaminophen (APAP)-induced hepatopathy models. Flow cytometric data further confirmed that an increase of F4/80+/ROS+ cells was dramatically decreased by SH-Man-HSA. The administration of SH-Man-HSA at 4 hours following a Con-A or APAP injection also exhibited profound hepato-protective action against two experimental hepatitis models, while this was not observed in the case of NAC. Therefore, SH-Man-HSA has a great potential for use as a rescue therapy for hepatopathy as a nano-antioxidant because of its efficient and rapid delivery of thiols to CD68+/CD206+ KC.