Hydrogen Peroxide‐Responsive Nanoparticle Reduces Myocardial Ischemia/Reperfusion Injury

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