Hydrogen peroxide-responsive copolyoxalate nanoparticles for detection and therapy of ischemia-reperfusion injury

The main culprit in the pathogenesis of ischemia/reperfusion (I/R) injury is the generation of high level of hydrogen peroxide (H₂O ₂). In this study, we report a novel diagnostic and therapeutic strategy for I/R injury based on H₂O₂-activatable copolyoxalate nanoparticles using a murine model of hind limb I/R injury. The nanoparticles are composed of hydroxybenzyl alcohol (HBA)-incorporating copolyoxalate (HPOX) that, in the presence of H₂O₂, degrades completely into three known and safe compounds, cyclohexanedimethanol, HBA and CO₂. HPOX effectively scavenges H₂O₂ in a dose-dependent manner and hydrolyzes to release HBA which exerts intrinsic antioxidant and anti-inflammatory activities both in vitro and in vivo models of hind limb I/R. HPOX nanoparticles loaded with fluorophore effectively and robustly image H₂O₂ generated in hind limb I/R injury, demonstrating their potential for bioimaging of H₂O ₂-associated diseases. Furthermore, HPOX nanoparticles loaded with anti-apoptotic drug effectively release the drug payload after I/R injury, exhibiting their effectiveness for a targeted drug delivery system for I/R injury. We anticipate that multifunctional HPOX nanoparticles have great potential as H₂O₂ imaging agents, therapeutics and drug delivery systems for H₂O₂-associated diseases.