Abstract 709: Encapsulation Of A Small Molecule p38 Inhibitor For Cardiac Regeneration
Myocardial dysfunction is usually progressive and successful therapy will likely require sustained delivery. Small molecule inhibitors have great clinical potential in the treatment of cardiac disease, but their size and stability make them difficult to target to the myocardium. SB239063 has been successful in preventing cardiovascular dysfunction but treatment protocols are prolonged and may not translate to larger animals. Polyketal (PK) particles are a new class of biomaterials that hydrolyze slowly at physiological pH values and degrade to non-toxic compounds. Here we show that polyketal-encapsulated SB239063 (PKSB) time-dependently inhibited TNF-α-induced p38 phosphorylation in RAW macrophages. In addition, PKSB, and not empty polyketals (PK), inhibited TNF-α stimulated extracellular superoxide production as measured by accumulation of superoxide-specific product of dihydroethidium, 2-hydroxyethidium (TNF 0.82μM; PKSB 0.37μM; p<0.05). To determine efficacy in vivo, we first established by skeletal muscle injection studies that polyketal treatment did not result in inflammation. We then performed a randomized and double-blinded study in rats subjected to myocardial infarction. Immediately following coronary artery ligation, rats were injected with PK, PKSB, or free SB239063 intramyocardially. Three days following infarction, there was a significant reduction in p38 phosphorylation within the infarct zone of PKSB rats, with no effect of PK or SB239063. In addition, only PKSB attenuated infarct-zone superoxide production (MI 27.68 μM; PKSB 8.49 μM; p<0.05) and TNF-α production (MI 157.73 pg/mg; PKSB 103.60 pg/mg; p<0.05). In a separate double-blinded study, we examined cardiac function by MRI at 7 and 21 days post treatment. While there was no difference at 7 days post-infarction, PKSB, and not PK or SB239063 significantly inhibited progression of dysfunction at 21 days. In summary, our data demonstrate that SB239063 retains its function following encapsulation and, in vivo following injury, performed significantly better than the free inhibitor or the control empty polymer. Thus, we conclude that polyketal encapsulation is a novel approach for delivering small, easily diffusible inhibitors for cardiac regeneration.