New regional drug delivery system by direct epicardial placement of slow-release prostacyclin agonist promise therapeutic angiogenesis in a porcine chronic myocardial infarction

Abstract

Although prostacyclin is an endogenous factor for the protection and regeneration of damaged tissue, the use of clinically available prostacyclin analogues for treating chronic pathological conditions is limited owing to their short half-lives. A new reagent, ONO-1301SR, which is a unique synthetic prostacyclin agonist polymerized with lactic and glycolic acid, has been demonstrated to constitutively release prostacyclin analogues to adjacent tissues, suggesting its therapeutic potential via slow-release delivery into a specific organ. In this study, we investigated the regenerative effect of direct epicardial delivery of the ONO-1301SR on a heart with a chronic myocardial infarct. An ameroid constrictor was placed on the left anterior descending coronary artery of Göttingen minipigs for 4 weeks to induce ischemic cardiomyopathy; this was followed by direct epicardial placement of ONO-1301SR-immersed gelatinous sheet, or only a gelatinous sheet on the anterolateral surface of the heart. Epicardial placement of ONO-1301SR resulted in significant recovery of global cardiac functions and regional wall motion of the lateral wall. Importantly, after epicardial placement of ONO-1301SR for 4 weeks, the myocardial blood flow significantly increased in the lateral region as assessed by 13N-ammonia positron emission tomography; this finding was consistent with significantly increased capillary density in the peri-infarct area with up-regulated angiogenic cytokine expression. Conclusion: Use of the slow-release drug delivery system of prostacyclin agonist yielded regenerative angiogenesis, including increased regional blood perfusion and systolic function in a porcine model of chronic myocardial infarction.