Abstract 15508: Detection and Therapy of Ischemia-Reperfusion Injury Using Hydrogen Peroxide-Activatable Polyoxalate Nanoparticles
The main culprit in the pathogenesis of ischemia/reperfusion (I/R) injury is the generation of high level of hydrogen peroxide (H2O2), which causes apoptosis and inflammation leading to cellular damage. In this study, we present 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.
Methods and Results: The nanoparticles are composed of hydroxybenzyl alcohol-incorporating copolyoxalate (HPOX) with average size of ~450nm. HPOX, in the presence of H2O2, degrades completely into three known and safe compounds, cyclohexanedimethanol, hydroxybenzyl alcohol and CO2. First, we loaded HPOX with rubrene (HPOX/Rb), a fluorophore. HPOX/Rb instantaneously generated strong light emission at 565 nm in presence of H2O2. We also found that HPOX scavenged H2O2 in a dose-dependent manner, with the intrinsic anti-oxidant and anti-inflammatory properties. To test the safety profile of HPOX, we administered HPOX (50 μ g/mice) daily for 7 days. There were no histological pathologies in various organs, and no renal or liver functional abnormalities. To test the bioimaging potential of HPOX, we injected HPOX/Rb distal to the I/R site in the hind limb. HPOX/Rb group generate a strong and robust light emission immediately, peaking at 2 min, and completely disappearing after 10 min of reperfusion. Co-administration of HPOX/Rb with catalase, H2O2-degrading enzyme, resulted in significant reduction in light emission that confirmed HPOX/Rb is specific for H2O2. Next, we used HPOX nanoparticles loaded with a potent PARP-1 inhibitor (HPOX/PI) to see if a drug encapsulated in HPOX nanoparticles are able to deliver drug in site-directed and time-specific manner. We found that HPOX/PI (50 μ g), but not HPOX alone, significantly decreased the I/R-induced PARP-1 and caspase-3 activities compared to the vehicle group after I/R. There was also significant attenuation of various inflammation markers, such as TNF-α and MCP-1, in HPOX/PI group.
Conclusion: Here, we present multifunctional nanoparticles that are able to image H2O2 in vivo, possess intrinsic anti-oxidant and anti-inflammatory properties, and capable of site directed drug delivery for the treatment of I/R injury.
- © 2011 by American Heart Association, Inc.