Myocardial Delivery of MMP Inhibiting Hydrogels

MMP 抑制水凝胶的心肌递送

• 批准号: 10217230
• 负责人: Brendan Purcell
• 金额: $ 99.47万
• 依托单位: PROHIBIX, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217230
• 关键词: Adopted; Affect; Area; Attenuated; Biological Sciences; Biotechnology; Blood; Caregivers; Catheters; Cells; Clinic; Clinical; Collaborations; Development; Dimensions; Dose; Dose-Limiting; Doxycycline; Drug Side Effects; Dyes; Echocardiography; Economic Burden; Encapsulated; Ensure; Enzymes; Epicardium; Extracellular Matrix; FDA approved; Family suidae; Fluorescent Dyes; Fluoroscopy; Formulation; Functional disorder; Funding; Gel; Goals; Harvest; Healthcare Systems; Heart; Heart failure; Histologic; Histology; Hydrogels; Individual; Infarction; Inflammatory; Inflammatory Response; Inhibition of Matrix Metalloproteinases Pathway; Injectable; Kinetics; Left; Left Ventricular Dysfunction; Left Ventricular Function; Left Ventricular Remodeling; Left ventricular structure; Legal patent; Magnetic Resonance Imaging; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Minimally Invasive Surgical Procedures; Modeling; Myocardial; Myocardial Infarction; Myocardium; Neutrophil Infiltration; Oral; Oral Administration; Outcome; Patient Care; Patients; Pennsylvania; Pericardial body location; Pericardial cavity; Pharmaceutical Preparations; Pharmacology; Phase; Play; Procedures; Process; Public Health; Research Design; Research Personnel; Research Proposals; Role; Safety; Small Business Innovation Research Grant; Structure; System; Technology; Therapeutic; Therapeutic Effect; Thinness; Time; Tissues; United States; Universities; Up-Regulation; Vascular blood supply; Ventricular; clinical translation; design; first-in-human; in vivo; industry partner; inhibitor/antagonist; innovation; meetings; novel; novel strategies; phase 1 study; pre-clinical; preclinical study; preservation; readmission rates; response; side effect; technology development; therapy outcome; tool

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.

抽象的 目前，美国超过300万人患有由 每年发生心肌梗死（MI）和超过600,000个可生存的MIS，其中包括200,000 ST段升高MIS（STEMIS）。斯蒂尼斯是由于长时间的严重MI 阻塞血液供应会影响大部分心肌。仍然存在重新住院率 STEMI患者的高高，在5年内，大约50％的STEMI患者将死亡。尽管 改善门与波隆时间以梗塞的梗塞，不利的左心室（LV） MI后发生重塑过程，导致对适应不良的变化对 LV。基质金属蛋白酶（MMP）是一类降解酶，有助于 LV壁变薄，扩展和最终的LV功能障碍。而系统给予MMP 抑制剂在保留LV结构和功能，剂量限制方面显示出令人鼓舞的结果 药物的作用停滞了临床翻译。 为了避免有希望的治疗剂（例如mmpis）的脱靶影响并提供有效的效果 宾夕法尼亚大学的梗塞，profribix LLC和研究人员的浓度 已经发明了一项突破性注射水凝胶技术，以封装和交付这些突破性的水凝胶技术 分子通过临床采用的心外膜进入程序。这种创新的水凝胶 系统，Epicargo，成功地输送到没有猪的心肌的目标区域 并发症并将荧光染料释放在I期研究中。另外，一本小说 开发了含有FDA批准的MMPI DoxyCycline的凝胶配方，以理想的形式开发 生物释放动力学。 Propibix LLC的这一II期建议旨在进一步验证 Epicargo凝胶在猪中的安全性和稳定性，并证明了局部强力霉素的功效 与药物的口服给药相比。成功完成提议的目标将进一步 验证该平台技术，以吸引生活科学投资者和行业合作伙伴资助 通过人类第一审判的发展。