H2O2-Activatable Antioxidant Polymeric Prodrug Nanoparticles for the Prevention of Renal Ischemia/Reperfusion Injury.

Abstract

Renal ischemia-reperfusion (IR) injury is an inevitable complication in various clinical settings including kidney transplantation and major vascular surgeries. Renal IR injury is a major risk factor for acute kidney injury, which still remains a major clinical challenge without effective therapy. The main cause of renal IR injury is the massive production of reactive oxygen species (ROS) including hydrogen peroxide (H2O2) that initiate inflammatory signaling pathways, leading to renal cell death. In this study, we developed fucoidan-coated polymeric prodrug (Fu-PVU73) nanoparticles as renal IR-targeting nanotherapeutics that can rapidly eliminate H2O2 and exert anti-inflammatory and antiapoptotic effects. Fu-PVU73 nanoparticles were composed of H2O2-activatable antioxidant and anti-inflammatory polymeric prodrug (PVU73) that incorporated H2O2-responsive peroxalate linkages, ursodeoxycholic acid (UDCA), and vanillyl alcohol (VA) in its backbone. Fu-PVU73 nanoparticles rapidly scavenged H2O2 and released UDCA and VA during H2O2-triggered degradation. In the study of renal IR injury mouse models, Fu-PVU73 nanoparticles preferentially accumulated in the IR injury-induced kidney and markedly protected the kidney from IR injury by suppressing the generation of ROS and the expression of proinflammatory cytokines. We anticipate that Fu-PVU73 nanoparticles have tremendous therapeutic potential for not only renal IR injury but also various ROS-associated inflammatory diseases.