Polyketals to encapsulate a small molecule p38 inhibitor for cardiac regeneration

描述：心力衰竭的主要原因是心肌梗死后心肌的局部丧失。由于组织的损失是高度局部化的，并且内源性反应不足以修复，因此最近的努力集中在使用各种治疗方案来预防初始细胞死亡。抑制p38激活与心肌梗死后的功能改善有关，然而抑制剂的大小使其难以在较大的动物中维持。该提案的目的是将SB239063（一种有效的p38磷酸化抑制剂）封装在聚缩酮颗粒内，以增强心肌保留并改善梗死后的功能。体内抑制剂研究和显性阴性小鼠方法证明了p38抑制治疗心肌梗死后心功能障碍的明显潜力;然而，抑制剂相对较小的尺寸限制了其在较大动物研究中的使用。聚缩酮颗粒是一类新的聚合物，其稳定，可降解为FDA批准的化合物，可以容易地进行修饰，并且可以在保持活性的同时封装蛋白质。该提议的中心假设是聚缩酮颗粒包封这种p38抑制剂并阻断心肌细胞的凋亡，以及防止心肌梗死后体外和体内巨噬细胞刺激的细胞因子释放。我们还相信，这种作用将扩展到内源性心脏干细胞，除了为植入的干细胞提供保护作用之外。该R01提案的成功完成将证明负载有这种小分子抑制剂的聚缩酮颗粒可用于治疗心肌梗死后的心功能障碍。我们进一步相信，该提议的完成也将证明聚缩酮包封的p38抑制作为细胞移植的辅助疗法的作用。考虑到心肌梗死后复杂的内源性反应，我们认为，从这个建议的数据将产生广泛的兴趣，使用聚缩酮心肌药物输送。 公共卫生相关性：充血性心力衰竭是世界范围内发病率和死亡率的主要原因，非常需要有效的治疗方案。我们建议使用一类称为聚缩酮的新型聚合物将SB239063（一种具有治疗潜力的强效p38抑制剂）直接封装并递送至心肌。这一提议将证明用聚缩酮抑制p38可用于帮助心肌梗死后的心脏组织再生。

DESCRIPTION: The major cause of heart failure is the regional loss of myocardium following myocardial infarction. Because the loss of tissue is highly localized, and the endogenous response is not sufficient for repair, recent efforts have focused on the prevention of initial cell death using a variety of treatment options. Inhibition of p38 activation has been associated with improved function following myocardial infarction, however the size of the inhibitor makes it difficult to sustain in larger animals. The objective of this proposal is to encapsulate SB239063, a potent inhibitor of p38 phosphorylation, within polyketal particles to enhance myocardial retention and improve function following infarction. In vivo inhibitor studies and dominant negative mouse approaches demonstrate a clear potential of p38 inhibition to treat cardiac dysfunction following myocardial infarction; however the relatively small size of the inhibitor has limited its use in larger animal studies. Polyketal particles are a new class of polymers that are stable, degrade in to FDA-approved compounds, can be modified easily and can encapsulate proteins while retaining activity. The central hypothesis of this proposal is that polyketal particles encapsulate this p38 inhibitor and block apoptosis of cardiac myocytes, as well as prevent stimulated cytokine release from macrophages both in vitro and in vivo following myocardial infarction. We also believe this effect will extend to endogenous cardiac stem cells, in addition to serving a protective role for implanted stem cells as well. The successful completion of this R01 proposal will demonstrate that polyketal particles loaded with this small molecule inhibitor can be used to treat cardiac dysfunction following myocardial infarction. We further believe completion of this proposal will also demonstrate a role for polyketal-encapsulated p38 inhibition as an adjunct therapy for cell transplantation. Given the complicated endogenous response following myocardial infarction, we believe that data from this proposal will generate widespread interest in using polyketals for myocardial drug delivery. PUBLIC HEALTH RELEVANCE: Congestive heart failure is a leading cause of morbidity and mortality worldwide and effective treatment options are greatly needed. We propose to encapsulate and deliver SB239063, a potent p38 inhibitor with therapeutic potential, directly to the myocardium using a new class of polymers called polyketals. This proposal will demonstrate that p38 inhibition with polyketals can be used to help regenerate cardiac tissue following myocardial infarction.