Biologically Selective Drug-Eluting Stent

生物选择性药物洗脱支架

• 批准号: 10183318
• 负责人: LAURA E NIKLASON
• 金额: $ 68.59万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10183318
• 关键词: Anticoagulation; Apoptosis; Aspirin; Binding; Biological; Bioreactors; Blood Vessels; Blood flow; CD95 Antigens; Cell Death; Cell Proliferation; Cell Survival; Cell surface; Cellular Metabolic Process; Cessation of life; Clinical; Complex; Computer Models; Coronary; Coronary Arteriosclerosis; Coronary artery; Diffusion; Dose; Effectiveness; Endothelial Cells; Endothelium; Ethylenes; Family suidae; Goals; Growth; Hemorrhage; Hyperplasia; In Vitro; Inhibition of Apoptosis; Injury; Investigation; Kinetics; Ligands; Measures; Mediating; Metals; Modeling; Myocardial Infarction; Nitric Oxide; Nitric Oxide Donors; Oryctolagus cuniculus; Patient risk; Patient-Focused Outcomes; Patients; Perfusion; Pharmaceutical Preparations; Platelet Activation; Plavix; Polymers; Receptor Cell; Resistance; Risk; SDZ RAD; Signal Transduction; Sirolimus; Smooth Muscle Myocytes; Stenosis; Stents; Thrombosis; Treatment Failure; Tumor Necrosis Factor Ligand Superfamily Member 6; Work; cell growth; cell injury; clopidogrel; combat; comparative; copolymer; design; efficacy evaluation; efficacy testing; iliac artery; improved; inhibitor/antagonist; injured; mTOR Inhibitor; mTOR inhibition; metallicity; next generation; novel; novel drug combination; patient safety; porcine model; pressure; prevent; receptor; response; restenosis; standard of care; stroke risk; thrombotic; vinyl acetate

ABSTRACT: Metallic stents are often used to restore blood flow in stenotic coronary arteries. Bare metal stent deployment under high pressure leads to vascular wall and smooth muscle cell (SMC) damage, with subsequent SMC proliferation, neointimal hyperplasia and treatment failure. To combat in-stent restenosis, drug-eluting stents delivering mTOR inhibitors such as sirolimus or everolimus, have become standard of care for coronary stenting. However, these stents typically require long-term dual anti-platelet therapy with aspirin and Plavix (clopidogrel), to prevent thrombotic occlusion of the stented arterial segment. This is due to the relatively non-specific action of mTOR inhibitors: endothelium does not efficiently recover after injury from DESs, rendering the stent struts and arterial lumen vulnerable to platelet activation and thrombosis. Unfortunately, long-term dual anti-platelet therapy leads to increased bleeding/stroke risk and, paradoxically, to increased risk of myocardial infarction. Therefore, finding an alternative drug elution strategy, that would spare endothelium while preventing re-stenosis, would be hugely beneficial to patients with coronary artery disease. Nitric oxide (NO⋅)-releasing stents, which are still under investigation, are attractive because their mechanism of action inhibits growth of SMC but not EC, and because NO⋅ has a very short diffusion distance, thereby limiting its effects to a localized region. However, to date no stent has succeeded in delivering sufficient doses of NO⋅ to reliably inhibit SMC growth. Since NO⋅ is a selective inhibitor of SMC, how can we increase its potency? For this work, we leverage the fact that NO⋅ increases Fas receptors on the SMC surface, while not having a similar effect on EC. Fas a death-inducing signaling complex upon binding to Fas ligand (FasL). Fas-mediated apoptosis of SMCs is known to decrease hyperplasia significantly in injured vessels. Indeed, the Fas-FasL interaction that kills SMC may create an even more potent DES than do mTOR inhibitors, since mTOR inhibition can arrest cell growth but may not cause apoptosis. Clinically, DES with better SMC inhibition are sorely needed, since current DES still suffer from significant rates of in-stent restenosis after 5 years. Since SMCs are significantly more sensitive to Fas-FasL interaction than are EC, we hypothesize that delivery of both FasL and NO by a next generation stent has the potential to potently block intimal hyperplasia, while retaining EC viability, more efficiently than other DES. This, in turn, could provide a way to shorten post-stent anticoagulation therapy and inhibit in-stent restenosis, thereby decreasing patient risk following coronary stent placement.

摘要： 金属支架通常用于恢复狭窄冠状动脉中的血流。裸金属支架 在高压下展开导致血管壁和平滑肌细胞（SMC）损伤， 随后SMC增殖、新生内膜增生和治疗失败。为了对抗支架内再狭窄， 递送mTOR抑制剂如西罗莫司或依维莫司的药物洗脱支架已成为标准治疗 用于冠状动脉支架植入术然而，这些支架通常需要长期的阿司匹林双重抗血小板治疗 和氯吡格雷，以防止支架动脉段的血栓性闭塞。这是由于 mTOR抑制剂的相对非特异性作用： DES，使支架支柱和动脉腔易于血小板活化和血栓形成。 不幸的是，长期双重抗血小板治疗导致出血/卒中风险增加，矛盾的是， 增加心肌梗死的风险。因此，找到一种替代药物洗脱策略， 内皮细胞，同时防止再狭窄，将是非常有益的患者与冠状动脉疾病。 一氧化氮（NO）释放支架仍在研究中， 作用机制抑制SMC而不是EC的生长，并且由于NO的扩散距离非常短， 从而将其影响限制在局部区域。然而，迄今为止，没有支架成功地输送 足够剂量的NO抑制剂以可靠地抑制SMC生长。由于NO是SMC的选择性抑制剂，我们如何 增强其效力？在这项工作中，我们利用了NO增加SMC上Fas受体的事实， 表面，而对EC没有类似的影响。Fas是一种与Fas结合的死亡诱导信号复合物 配体（FasL）。已知Fas介导的SMC凋亡可显著减少损伤组织中的增生。 船舶.事实上，杀死SMC的Fas-FasL相互作用可能产生比mTOR更有效的DES 抑制剂，因为mTOR抑制可以阻止细胞生长，但可能不会引起细胞凋亡。临床上，DES 由于目前的药物洗脱支架仍然存在显著的支架内平滑肌细胞增殖率， 5年后再狭窄。由于SMC对Fas-FasL相互作用比EC明显更敏感，因此我们 假设通过下一代支架递送FasL和NO两者具有有效阻断 内膜增生，同时保持EC活力，比其他DES更有效。这反过来又可以提供一个 缩短支架后抗凝治疗和抑制支架内再狭窄的方法，从而减少患者 冠状动脉支架置入后的风险。