Development of novel adenosine polymers for coating medical devices

开发用于涂覆医疗器械的新型腺苷聚合物

• 批准号: 8057469
• 负责人: Mervyn B. Forman
• 金额: $ 18.3万
• 依托单位: NUVIEW LIFE SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8057469
• 关键词: Acute; Adenosine; Adherence; Animal Model; Animals; Arteries; Attenuated; Balloon Angioplasty; Bathing; Blood; Blood Vessels; Blood flow; Clinical; Clinical Research; Complex; Continuous Infusion; Coronary Arteriosclerosis; Coronary Vessels; Coronary artery; Cysteine; Development; Devices; Disease; Dose; Electron Microscopy; Family suidae; Gel Chromatography; Generations; Glass; Glycerol; Half-Life; Hemolysis; High Pressure Liquid Chromatography; In Vitro; Infarction; Injury; Intravenous; Kinetics; Lesion; Measures; Medical Device; Methodology; Molecular Weight; Myocardial; Myocardial Infarction; Nuclear Magnetic Resonance; Nucleosides; Organ; Outcome; Pathogenesis; Patients; Perfusion; Pharmaceutical Preparations; Phase; Physiological; Polyethylene Glycols; Polymers; Polyurethanes; Prevention; Procedures; Reaction; Recurrence; Saphenous Vein; Screening procedure; Simulate; Site; Stenosis; Sterilization; Structure; System; Temperature; Testing; Therapeutic; Time; Tissues; Toxicity Tests; Transition Temperature; Ventricular Function; Water; base; cytotoxicity; cytotoxicity test; extracellular; improved; in vivo; meetings; monomer; mortality; novel; percutaneous coronary intervention; phase 2 study; polymerization; prophylactic; receptor; research study; restoration; success; vascular bed

DESCRIPTION (provided by applicant): Percutaneous coronary intervention (PCI) is the most frequently employed strategy to revascularize atherosclerotic stenosis of native coronary arteries and saphenous vein grafts. Tissue perfusion is frequently impaired following PCI, particularly in patients with ST segment elevation myocardial infarction (STEMI). This results in the "no-reflow" phenomenon which is an important predictor of mortality. Adenosine is an endogenous nucleoside that attenuates many of the mechanisms responsible for the "no-reflow" phenomenon. Experimental and clinical studies have confirmed adenosine's efficacy in enhancing myocardial salvage and improving microvascular blood flow. Adensoine's full therapeutic potential is compromised due to its ultra short half life requiring large doses to obtain adequate blood levels at the target organ. Since the guidewire is the first PCI device that perturbs the vascular bed, we have developed the concept of elution of adenosine continuously via an adenosine-polymer-coated guidewire. We have developed a number of unique physiologic polymers in which adenosine can be covalently incorporated and placed on a guidewire. We tested out first generation polymers (LDI-glycerol and LDI-adenosine) in a small animal model and verified that it resulted in a substantial increase in blood flow. However in a large animal model the kinetic profile was too rapid for a typical interventional procedure (~45 mins). We have subsequently developed two new polymers, LDI- cysteine and LDI-PEG. Prior to initiating large animal studies in a Phase 2 study it is imperative we optimize the polymer structure, guidewire-coating methodology and kinetic release profile. We therefore propose the following studies with the new polymers to identify an ideal product. First we will develop and characterize the structure of the polymers and permutations thereof and evaluate numerous coating methodologies to optimize release kinetic profile. Second we will evaluate adenosine elution utilizing a temperature controlled recirculating water bath system and measure adenosine release serially with HPLC. Third we will determine if the selected polymer is safe for clinical use by employing NAMSA- based screening tests for cytotoxicity, pyrogenicity, hemolysis, and sensitization. Finally we will evaluate the stability and durability of the polymer with glass transition temperature experiments and by passing coated wires through simulated lesions. If the "anti-no-reflow" wire is shown to be effective in improving outcomes after interventional procedures it will represent a major advance in the treatment of patients with coronary artery disease undergoing PCI. This will have important societal benefits due to the large number of interventional procedures performed in the US each year for coronary artery disease. PUBLIC HEALTH RELEVANCE: The improved outcomes that may potentially occur with the device would have important societal benefits due to the large number of interventional procedures performed in the US each year for atherosclerotic disease.

描述（由申请人提供）：经皮冠状动脉介入治疗（PCI）是最常用的对自体冠状动脉和隐静脉移植物的动脉粥样硬化性狭窄进行血运重建的策略。 PCI 后组织灌注经常受损，尤其是 ST 段抬高型心肌梗死 (STEMI) 患者。这导致“无复流”现象，这是死亡率的重要预测指标。腺苷是一种内源性核苷，可减弱许多导致“无回流”现象的机制。实验和临床研究已证实腺苷具有增强心肌挽救和改善微血管血流的功效。由于腺素半衰期超短，需要大剂量才能在靶器官获得足够的血液浓度，因此其全部治疗潜力受到损害。由于导丝是第一个干扰血管床的 PCI 设备，因此我们开发了通过腺苷聚合物涂层导丝连续洗脱腺苷的概念。我们开发了许多独特的生理聚合物，其中腺苷可以共价结合并放置在导丝上。我们在小动物模型中测试了第一代聚合物（LDI-甘油和 LDI-腺苷），并验证它会导致血流量大幅增加。然而，在大型动物模型中，动力学曲线对于典型的介入手术来说太快（约 45 分钟）。我们随后开发了两种新的聚合物，LDI-半胱氨酸和LDI-PEG。在第二阶段研究中启动大型动物研究之前，我们必须优化聚合物结构、导丝涂层方法和动力学释放曲线。因此，我们建议对新聚合物进行以下研究，以确定理想的产品。首先，我们将开发和表征聚合物的结构及其排列，并评估多种包衣方法以优化释放动力学曲线。其次，我们将利用温控循环水浴系统评估腺​​苷洗脱，并使用 HPLC 连续测量腺苷释放。第三，我们将通过采用基于 NAMSA 的细胞毒性、热原性、溶血性和致敏性筛选测试来确定所选聚合物是否可以安全用于临床。最后，我们将通过玻璃化转变温度实验以及将涂层线穿过模拟损伤来评估聚合物的稳定性和耐久性。如果“防无复流”导丝被证明能够有效改善介入手术后的结果，这将代表着接受 PCI 的冠状动脉疾病患者治疗的重大进步。由于美国每年针对冠状动脉疾病进行大量介入手术，这将产生重要的社会效益。 公共健康相关性：由于美国每年针对动脉粥样硬化疾病进行大量介入手术，因此该设备可能带来的改善结果将产生重要的社会效益。

项目成果

Development of a novel adenosine-eluting guidewire (Adenowire) for coronary vasodilation during percutaneous coronary intervention.

开发一种新型腺苷洗脱导丝（Adenowire），用于经皮冠状动脉介入治疗期间的冠状血管舒张。

• 发表时间: 2014-03-20
• 作者: Forman, Mervyn B;Zhang, Jianying;Wu, Shaoxoing;Mi, Zaichuan;Hou, Dongming;Jackson, Edwin K
• 通讯作者: Jackson, Edwin K