Development of Novel Adenosine Polymers for Coating Medical Devices

用于医疗器械涂层的新型腺苷聚合物的开发

• 批准号: 9407582
• 负责人: Mervyn B. Forman
• 金额: $ 68.36万
• 依托单位: ADENOPAINT, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-10 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9407582
• 关键词: Accounting; Adenosine; Adhesions; Advanced Development; Alleles; American; Animal Model; Anterior; Applications Grants; Area; Arterial Fatty Streak; Atherosclerosis; Attenuated; Biochemical Pathway; Blood; Blood Platelets; Blood Vessels; Blood flow; Calorimetry; Cardiotonic Agents; Catheters; Cause of Death; Clinical; Clinical Research; Clinical Trials; Complex; Continuous Infusion; Coronary; Coronary Arteriosclerosis; Coronary Circulation; Coronary Vessels; Coronary artery; Data; Development; Devices; Economics; Electron Microscopy; Elements; Employee Strikes; Endothelial Cells; Ensure; Evaluation; Exhibits; Family suidae; Fibrin; Genetic; Genetic Engineering; Goals; Half-Life; Heterozygote; Human; Hydrolysis; In Vitro; Industry; Infarction; Intravenous; Ischemia; Knock-out; Laboratories; Lesion; Low Density Lipoprotein Receptor; Maintenance; Measurement; Medical Device; Microcirculation; Microcirculatory Bed; Microvascular Dysfunction; Modality; Modeling; Muscle Cells; Myocardial; Myocardial Infarction; Necrosis; Nucleosides; Obstruction; Outcome; Patients; Performance; Perfusion; Pharmacology; Phase; Physiological; Polymers; Prevention; Procedures; Production; Reperfusion Injury; Reperfusion Therapy; Safety; Saphenous Vein; Seminal; Site; Smooth Muscle; Spectrometry; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Stenosis; Sterilization; Structure; Testing; Therapeutic; Thinness; Time; Tissues; Vasoconstrictor Agents; Vasodilation; Vein graft; Ventricular Function; biomaterial compatibility; clinical application; design; endothelial dysfunction; experimental study; hypercholesterolemia; improved; improved outcome; in vivo; low density lipoprotein inhibitor; mortality; new technology; novel; percutaneous coronary intervention; prevent; receptor; success; vascular bed; vasoconstriction; western diet

Project Summary Myocardial infarction (MI) occurs in ~900,000 Americans annually accounting for a mortality of 7-18%. While percutaneous coronary intervention (PCI) is invariably successful in restoring epicardial patency, significant microvascular obstruction (MVO) resulting in the “no-reflow phenomenon” (NRF) occurs frequently which significantly impacts mortality and the development of CHF. Current devices are only partially effective in mitigating MVO and NRF following PCI for MI. Adenosine attenuates many of the mechanisms responsible for MVO and NRF. Seminal studies in our laboratory demonstrated that intravenous adenosine resulted in striking vascular and myocardial protection and this was subsequently confirmed in large clinical trials. Adenosine’s full potential is compromised due to its ultra-short half-life. Since the guidewire is the first PCI device deployed into the coronary vascular bed, we developed a simple, two-step procedure to make a pentameric form of adenosine (PA) that can be coated onto guidewires (Adenowire) and allows for continuous and sustained elution of adenosine into the coronary circulation during PCI. We validated the structure of PA with NMR, its stability by calorimetry and confirmed its safety with biocompatibility tests. We also demonstrated that PA released adenosine in vitro over 60 mins. Porcine studies demonstrated that pharmacologically active amounts of adenosine are released as verified by a significant and sustained increase in coronary blood flow following wire insertion. Since our initial submission of this grant proposal we have developed strong relationships with industry leading guidewire and coating companies resulting in the production of a viable commercial product. The goal of this Phase II application is to advance this novel technology to the clinical arena. We will utilize a LDLR knockout swine model which manifests hypercholesterolemia and human-like atherosclerotic lesions. Two important mechanisms of MVO will be tested: 1) efficacy of Adenowire to reverse potent smooth muscle vasoconstrictors; and 2) effect of Adenowire to ameliorate cellular obstruction by endothelial cells and formed elements thereby attenuating NRF following regional ischemia and reperfusion. The data obtained from these studies will be invaluable in advancing this highly novel guidewire device to clinical trials. The concept is transformative and has a high likelihood of success since it will deliver high concentrations of adenosine directly at the target site throughout the PCI procedure. If clinical trials confirm that Adenowire is effective in preventing MVO and NRF it would represent a major advance in treatment of MI patients. This would have important societal and economic benefits for MI patients treated with PCI in the US each year.

项目摘要 心肌梗死（MI）每年发生在约900，000名美国人中，占死亡率的7- 18%。 虽然经皮冠状动脉介入治疗（PCI）总是成功地恢复心外膜通畅， 无复流现象是一种常见的微血管阻塞现象 其显著影响死亡率和CHF的发展。目前的设备仅部分有效， 减轻MI经皮冠状动脉介入治疗后的MVO和NRF。 腺苷减弱了许多负责MVO和NRF的机制。我们的精液研究 实验室证明，静脉注射腺苷可显著保护血管和心肌 这随后在大型临床试验中得到证实。腺苷的全部潜力受到损害， 超短半衰期由于导丝是第一个在冠状动脉血管床内展开的PCI器械，我们 开发了一种简单的两步法来制备五聚体形式的腺苷（PA）， 导丝（Adenowire），并允许腺苷持续洗脱至冠状动脉 PCI期间的循环。我们用核磁共振法验证了PA的结构，用量热法验证了PA的稳定性， 生物相容性测试的安全性。我们还证明了PA在体外释放腺苷超过60分钟。 猪的研究表明，释放的腺苷活性量， 导丝插入后冠状动脉血流量显著且持续增加。自从我们首次提交 在这项拨款提案中，我们与行业领先的导丝和涂层公司建立了牢固的关系。 生产出一种可行的商业产品。 该II期申请的目标是将这种新技术推向临床竞技场。我们将 利用表现出高胆固醇血症和类人动脉粥样硬化的LDLR敲除猪模型 病变将检测MVO的两种重要机制：1）Adenowire逆转有效平滑 肌肉血管收缩剂;和2）Adenowire改善内皮细胞引起的细胞阻塞的作用， 从而在局部缺血和再灌注后减弱NRF。 从这些研究中获得的数据对于推进这种高度新颖的导丝装置将是非常宝贵的 临床试验这个概念是变革性的，成功的可能性很高，因为它将提供高质量的服务。 在整个PCI过程中，直接在靶部位处的腺苷浓度。如果临床试验证实 Adenowire可有效预防MVO和NRF，这将代表MI治疗的重大进展 患者这将为美国接受PCI治疗的MI患者带来重要的社会和经济效益 每年.