Myocardial Delivery of MMP Inhibiting Hydrogels

摘要 目前，美国有超过300万人患有心力衰竭， 每年发生心肌梗死（MI）和超过60万例存活MI，其中包括20万例 ST段抬高MI（STEMI）。STEMI是一种严重的心肌梗死， 影响大面积心肌的血液供应受阻。再次住院率仍然 STEMI患者的死亡率更高，并且在5年内，大约50%的STEMI患者将死亡。尽管 改善门到球囊时间再灌注梗死，不良左心室（LV） 心肌梗死后发生重塑过程，导致心肌结构和功能的适应不良变化， 的LV。基质金属蛋白酶（MMP）是一类组织降解酶，其有助于 左室壁变薄、扩张，最终导致左室功能障碍。当全身施用MMP时， 抑制剂在保护LV结构和功能、剂量限制性方面显示出有希望的结果， 这些药物的效果已经停止了临床转化。 为了避免有前途的治疗剂如MMPI的脱靶效应，并提供有效的治疗， 浓度局部梗死，Prohibix有限责任公司和宾夕法尼亚大学的研究人员 发明了一种突破性的可注射水凝胶技术， 分子通过临床采用的心外膜进入程序。这种创新的水凝胶 EPICARGO系统成功输送至猪心肌靶区， 并发症和局部释放的荧光染料在第一阶段的研究。此外，一部小说 凝胶制剂含有FDA批准的MMPI，强力霉素，开发了理想的 生物响应释放动力学Prohibix LLC的第二阶段提案旨在进一步验证 EPICARGO凝胶在猪中的安全性和稳定性，并证明局部多西环素的有效性 与药物的口服给药相比，成功实现拟议目标将进一步 验证该平台技术，以吸引生命科学投资者和行业合作伙伴提供资金 通过首次人体试验进行开发。

ABSTRACT Over 3 million people in the United States currently suffer from heart failure caused by a myocardial infarction (MI) and more than 600,000 survivable MIs occur each year, including 200,000 ST-segment Elevated MIs (STEMIs). STEMIs are a severe MI caused by a prolonged period of blocked blood supply that affects a large area of the heart muscle. Re-hospitalization rates remain high for STEMI patients and within 5 years approximately 50% of STEMI patients will die. Despite improvements in door-to-balloon times to reperfuse the infarct, an adverse left ventricular (LV) remodeling process occurs post MI that leads to maladaptive changes to the structure and function of the LV. Matrix metalloproteinases (MMPs) are a class of tissue degrading enzymes that contribute to LV wall thinning, expansion and ultimately LV dysfunction. While systemic administration of MMP inhibitors has shown promising results in preserving LV structure and function, dose-limiting side effects of the drugs have stalled clinical translation. To avoid off-target effects of promising therapeutics such as MMPIs and deliver effective concentrations locally to the infarct, Prohibix LLC and investigators at the University of Pennsylvania have invented a breakthrough injectable hydrogel technology to encapsulate and deliver these molecules through a clinically adopted, epicardial access procedure. This innovative hydrogel system, EPICARGO, was successfully delivered to a target region of the myocardium in pigs without complications and localized the release of a fluorescent dye in Phase I studies. In addition, a novel gel formulation containing the FDA approved MMPI, doxycycline, was developed with ideal bioresponsive release kinetics. This Phase II proposal by Prohibix LLC seeks to further validate the safety and stability of EPICARGO gels in pigs, and demonstrate efficacy of localized doxycycline delivery compared to oral dosing of the drug. Successful completion of the proposed Aims will further validate this platform technology in order to attract life science investors and industry partners to fund development through first-in-man trials.