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.

项目概要 每年约有 900,000 名美国人患有心肌梗塞 (MI)，死亡率为 7-18%。 虽然经皮冠状动脉介入治疗 (PCI) 总是能成功恢复心外膜通畅， 严重的微血管阻塞（MVO）导致“无复流现象”（NRF）频繁发生 这对死亡率和 CHF 的发展有显着影响，目前的设备仅部分有效。 在 MI 的 PCI 之后减轻 MVO 和 NRF。 在我们的研讨会研究中，腺苷会减弱许多导致 MVO 和 NRF 的机制。 实验室证明静脉注射腺苷可产生显着的血管和心肌保护作用 随后大型临床试验证实了这一点，因为腺苷的全部潜力受到了损害。 由于导丝是第一个部署到冠状血管床中的 PCI 设备，因此我们的半衰期超短。 开发了一种简单的两步程序来制备五聚形式的腺苷（PA），可以将其涂覆在 导丝（腺线）并允许将腺苷连续且持续地洗脱到冠状动脉中 我们通过 NMR 验证了 PA 的结构，通过量热法验证了其稳定性，并确认了其稳定性。 我们还通过生物相容性测试证明了 PA 在体外 60 分钟内释放腺苷。 猪研究表明，释放出药理活性量的腺苷，经证实 自我们首次提交以来，冠状动脉血流量显着且持续增加。 在这项拨款提案中，我们与行业领先的导丝和涂层建立了牢固的关系 从而生产出可行的商业产品的公司。 二期应用的目标是将这项新技术推向临床领域。 利用 LDLR 敲除猪模型，该模型表现出高胆固醇血症和类人动脉粥样硬化 将测试 MVO 的两个重要机制：1）Adenwire 逆转平滑肌的功效。 肌肉血管收缩剂；2) Adenwire 改善内皮细胞的细胞阻塞的作用； 形成的元素从而减弱局部缺血和再灌注后的 NRF。 从这些研究中获得的数据对于高度推进这种新型导丝装置具有无价的价值 这个概念具有变革性，并且成功的可能性很高，因为它会带来很高的效果。 如果临床试验证实，则在整个 PCI 过程中直接在目标部位检测腺苷浓度。 Adenowire 可有效预防 MVO 和 NRF，这将代表 MI 治疗的重大进步 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。