Ischemia/reperfusion (IR) injury is induced by the restoration of blood flow to the prolonged ischemic tissues and is considered as the paradoxical exacerbation of ischemic damages. A large amount of reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) produced immediately after reperfusion induces oxidative stress, which plays an essential role in the pathogenesis of IR injury. It is therefore critical to suppress oxidative stress for the prevention and treatment of IR injury. Ursodeoxycholic acid (UDCA), one of the tertiary bile acids, promotes the generation of antioxidant glutathione (GSH) and also exerts hepatoprotective, cytoprotective, and antiapoptotic effects. However, the clinical uses of UDCA are limited mainly by its poor water solubility and low bioavailability. In this study, by exploiting the concept of self-assembling disulfide-bridged dimeric prodrugs, we developed a disulfide-bridged UDCA dimer (ssUDCA) as a therapeutic agent of hepatic IR injury. ssUDCA could self-assemble into stable nanospheres under aqueous conditions, scavenge H2O2, and exert anti-inflammatory and antiapoptotic activities. In a mouse model of hepatic IR injury, ssUDCA (5 mg/kg) significantly alleviated the IR injury by suppressing ROS production and inhibiting proinflammatory cytokines. Therefore, our findings offer a promising strategy for the effective treatment of hepatic IR injury and also provide deep insights into the impact of disulfide-bridged UDCA nanoassemblies in pharmaceutical applications.
Keywords: ischemia−reperfusion injury; nanoassembly; prodrug; reactive oxygen species; ursodeoxycholic acid.