Abstract 3086: Delivery of SOD With Polyketal Particles Protects Rats From Acute Myocardial Infarction
Oxidative stress is increased in the myocardium following infarction, playing significant roles in cardiac myocyte death and loss of cardiac function. Superoxide dismutase (SOD) protein therapy may have broad clinical implications; however intracellular delivery and poor delivery kinetics are critical obstacles. Polyketal particles are a new class of biomaterials with controllable kinetics that degrade into FDA-approved compounds. SOD was encapsulated with 50% efficiency within polyketal microparticles (PK-SOD). Scavenging capability of PK-SOD was tested by measuring superoxide production of PMA-stimulated macrophages in the presence of either empty microparticles (PK) or PK-SOD. Both extracellular and intracellular superoxide were dose-dependently scavenged only by PK-SOD treatment suggesting that quite interestingly, our polymer can deliver antioxidant proteins intracellularly. To determine if PK-SOD could also scavenge reactive oxygen species in vivo, we used a rat model of ischemia/reperfusion (I/R) followed by particle injection. Prior studies done in mice and rats demonstrated favorable retention and biocompatibility of the particles. Rats were injected with either PK or PK-SOD in a randomized manner and oxidative stress in the infarct zone was measured after 3 days by cytochrome C. Three days following I/R injury there was a significant increase in superoxide levels in control rats (p<0.05). While there was no effect of PK, PK-SOD significantly reduced these values to sham levels (p<0.05 vs. I/R). To localize the superoxide scavenging, frozen sections were made and dihydroethidium (DHE) staining was performed. We found a significant increase in DHE staining in the border zones of the infarct that was significantly reduced by only PK-SOD (p<0.05). We also found a significant decrease in myocyte apoptosis as measured by TUNEL staining (p<0.05). Finally, we measured cardiac function by echocardiography at baseline and 3 days following I/R. We found a significant reduction in function following I/R that was completely abrogated by PK-SOD treatment (p<0.01), and no effect of free SOD or empty PK. These results demonstrate the potential of polyketal particles to deliver enzymatic proteins for the treatment of cardiac dysfunction.