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局部心肌的丢失。由于组织的丢失是高度局部性的，内源性反应不足以修复，最近的努力集中在使用各种治疗方案来预防最初的细胞死亡。抑制p38的激活与心肌梗死后功能的改善有关，但该抑制物的大小使其难以在更大的动物中维持。该提案的目的是将有效的p38磷酸化抑制剂SB239063包裹在聚酮颗粒中，以增强心肌滞留和改善心肌梗死后的功能。体内抑制剂研究和显性阴性小鼠方法表明，p38抑制明显有可能治疗心肌梗死后的心功能障碍；然而，该抑制剂相对较小的体积限制了其在更大动物试验中的使用。聚酮缩醛颗粒是一种新型聚合物，它稳定，可降解成FDA批准的化合物，易于修饰，并能在保持活性的同时包裹蛋白质。这一建议的中心假设是聚酮颗粒包裹这种p38抑制物，阻断心肌细胞的凋亡，并在体外和体内阻止心肌梗死后巨噬细胞刺激的细胞因子释放。我们还认为，除了对移植的干细胞起到保护作用外，这种作用还将延伸到内源性心脏干细胞。R01提案的成功完成将证明，装载这种小分子抑制剂的聚酮颗粒可以用于治疗心肌梗死后的心功能障碍。我们进一步相信，这项提议的完成也将展示聚酮包埋的p38抑制作为细胞移植辅助治疗的作用。考虑到心肌梗死后复杂的内源性反应，我们相信，这项提议的数据将引起人们对使用聚酮类药物进行心肌药物输送的广泛兴趣。 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。我们建议使用一种名为聚酮的新型聚合物将具有治疗潜力的有效p38抑制剂SB239063包裹并直接输送到心肌。这项提议将证明用聚酮抑制p38可以用来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.