Polyketals to encapsulate a small molecule p38 inhibitor for cardiac regeneration

聚缩酮封装用于心脏再生的小分子 p38 抑制剂

• 批准号: 7788138
• 负责人: Michael E Davis
• 金额: $ 36.92万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7788138
• 关键词: Acute; Acute myocardial infarction; Adult; Affect; Angioplasty; Animals; Anticoagulants; Apoptosis; Area; Biocompatible Materials; Cardiac; Cardiac Myocytes; Cell Death; Cell Survival; Cell Therapy; Cell Transplantation; Cells; Cessation of life; Chronic; Collagen; Congestive Heart Failure; Coronary artery; Cultured Cells; Data; Diffusion; Dominant-Negative Mutation; Dose; Double-Blind Method; Drug Delivery Systems; Echocardiography; Encapsulated; FDA approved; Fibrosis; Functional disorder; Germ Cells; Growth; Heart; Heart failure; Hospitals; Human; Hydrolysis; Immunohistochemistry; Implant; In Vitro; Infarction; Inflammation; Inflammatory; Injection of therapeutic agent; Intervention; Ligation; MAP Kinase Gene; MAPK14 gene; Magnetic Resonance Imaging; Measures; Morbidity - disease rate; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Neonatal; Organ Transplantation; Outcome; Pathway interactions; Patients; Peptides; Phosphorylation; Phosphotransferases; Physiological; Polymers; Prevention; Process; Production; Progressive Disease; Proteins; Publishing; Randomized; Rattus; Rodent; Role; Signal Pathway; Site; Staining method; Stains; Stem cells; Superoxides; Testing; Therapeutic; Time; Tissues; Transforming Growth Factors; Transgenic Mice; Translating; Transplant Recipients; Transplantation; Ventricular; base; connective tissue growth factor; cytokine; effective therapy; gene therapy; improved; improved functioning; in vivo; inhibitor/antagonist; interest; kinase inhibitor; macrophage; mortality; mouse model; nanofiber; particle; prevent; public health relevance; repaired; response; small molecule; stem cell niche; stem cell population

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.

描述：心力衰竭的主要原因是心肌梗塞后心肌的局部损失。由于组织损失是高度局部化的，并且内源性反应不足以进行修复，因此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。 p38 激活的抑制与心肌梗塞后功能的改善有关，但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 p38 磷酸化的有效抑制剂）封装在聚缩酮颗粒内，以增强心肌滞留并改善梗塞后的功能。体内抑制剂研究和显性失活小鼠方法表明 p38 抑制具有治疗心肌梗塞后心功能障碍的明显潜力；然而，该抑制剂相对较小的尺寸限制了其在大型动物研究中的使用。聚缩酮颗粒是一类新型聚合物，它很稳定，可以降解为 FDA 批准的化合物，可以轻松修饰，并且可以在保留活性的同时封装蛋白质。该提议的中心假设是聚缩酮颗粒封装了这种 p38 抑制剂并阻止心肌细胞凋亡，并防止心肌梗塞后体外和体内巨噬细胞刺激的细胞因子释放。我们还相信，除了对植入的干细胞起到保护作用外，这种效应还将延伸到内源性心脏干细胞。该R01提案的成功完成将证明负载这种小分子抑制剂的聚缩酮颗粒可用于治疗心肌梗塞后的心脏功能障碍。我们进一步相信，该提案的完成还将证明聚缩酮封装的 p38 抑制作为细胞移植辅助疗法的作用。考虑到心肌梗塞后复杂的内源性反应，我们相信该提案的数据将引起人们对使用聚缩酮进行心肌药物输送的广泛兴趣。 公共卫生相关性：充血性心力衰竭是全世界发病和死亡的主要原因，非常需要有效的治疗方案。我们建议使用一种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）封装并直接递送至心肌。该提案将证明聚缩酮抑制 p38 可用于帮助心肌梗塞后心脏组织再生。