Hydrogen Peroxide‐Responsive Nanoparticle Reduces Myocardial Ischemia/Reperfusion Injury

Abstract

Background During myocardial ischemia/reperfusion (I/R), a large amount of reactive oxygen species ( ROS ) is produced. In particular, overproduction of hydrogen peroxide (H 2 O 2 ) is considered to be a main cause of I/R‐mediated tissue damage. We generated novel H 2 O 2 ‐responsive antioxidant polymer nanoparticles ( PVAX and HPOX ) that are able to target the site of ROS overproduction and attenuate the oxidative stress‐associated diseases. In this study, nanoparticles were examined for their therapeutic effect on myocardial I/R injury. Methods and Results The therapeutic effect of nanoparticles during cardiac I/R was evaluated in mice. A single dose of PVAX (3 mg/kg) showed a significant improvement in both cardiac output and fraction shortening compared with poly(lactic‐coglycolic acid) ( PLGA ) particle, a non‐H 2 O 2 ‐activatable nanoparticle. PVAX also significantly reduced the myocardial infarction/area compared with PLGA (48.7±4.2 vs 14.5±2.1). In addition, PVAX effectively reduced caspase‐3 activation and TUNEL ‐positive cells compared with PLGA . Furthermore, PVAX significantly decreased TNF ‐α and MCP ‐1 m RNA levels. To explore the antioxidant effect of PVAX by scavenging ROS , dihydroethidium staining was used as an indicator of ROS generation. PVAX effectively suppressed the generation of ROS caused by I/R, whereas a number of dihydroethidium‐positive cells were observed in a group with PLGA I/R. In addition, PVAX significantly reduced the level of NADPH oxidase ( NOX ) 2 and 4 expression, which favors the reduction in ROS generation after I/R. Conclusions Taken together, these results suggest that H 2 O 2 ‐responsive antioxidant PVAX has tremendous potential as a therapeutic agent for myocardial I/R injury.