Targeted Delivery of Cardioprotective Drugs

心脏保护药物的靶向递送

• 批准号: 8010049
• 负责人: Marina V Backer
• 金额: $ 38.55万
• 依托单位: SIBTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-20 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8010049
• 关键词: Acute myocardial infarction; Adverse effects; Angioplasty; Annexins; Anterior Descending Coronary Artery; Apoptosis; Apoptotic; Binding; Biodistribution; Cardiac; Cardiac Myocytes; Cells; Collaborations; Connecticut; Coupled; Cyclosporine; Data; Dose; Drug Delivery Systems; Drug Formulations; Drug Stability; Encapsulated; Fluorescence; Health; Human; Human Engineering; Immunohistochemistry; Immunosuppressive Agents; In Vitro; Infarction; Injection of therapeutic agent; Injury; Left; Ligation; Lip structure; Liposomes; Mediating; Modeling; Mortality Determinants; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Organ; Outcome; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phase; Phosphatidylserines; Probability; Rattus; Recovery of Function; Regimen; Reperfusion Injury; Reperfusion Therapy; Staging; Surface; Testing; Therapeutic; Toxic effect; Toxicology; Universities; Work; annexin A5; base; disabling disease; improved; in vivo; injured; intravenous administration; mouse model; new technology; novel strategies; protective effect; public health relevance; research study; standard of care; targeted delivery; therapeutic target; tissue culture

DESCRIPTION (provided by applicant): Myocardial infarction is a disabling disease, with infarct size being a major determinant of mortality. To limit infarct size and improve functional recovery, the ischemic myocardium has to be reperfused. However, reperfusion itself causes irreversible damage to the previously ischemic myocardium. A significant part of cardiac injury is caused by apoptosis that starts immediately at the beginning of reperfusion. Therefore, reperfusion injury is considered an important new pharmacologic target for the treatment of patients with ongoing acute myocardial infarction. We propose to develop a targeted liposomal formulation of two drugs proven to protect myocardium through independent mechanisms. Drug-carrying liposomes will be decorated with human annexin V for targeting to phosphatidylserine exposed on the surface of cardiomyocytes at the early stages of apoptosis. Intravenous administration of such liposomes immediately before the beginning of reperfusion could serve as an adjunct therapy for angioplasty and/or thrombolytic administration, which are the standard of care for patients with myocardial infarction. The advantages of the proposed strategy are: 1) delivery of pharmacologically significant amounts of drugs in cardiomyocytes from the first moments of reperfusion, when apoptosis is still reversible, 2) avoiding adverse effects of high-dose regimens that are necessary for free drugs, and 3) intracellular delivery of two drugs working via independent mechanisms increases the probability of successful treatment. Targeted drug-loaded liposomes will be evaluated in primary cultures of cardiomyocytes. We will establish mechanism(s) of internalization in early apoptotic cells and evaluate the therapeutic potential of annexin-targeted drug-loaded liposomes. Biodistribution, targeted drug delivery and the protective effects of the liposomes in vivo will be studied in a mouse model of myocardial ischemia/reperfusion. If successful, the proposed strategy will establish the feasibility of using annexin- targeted therapeutic liposomes as an adjunct therapy for myocardial infarction. It will also advance new technologies in developing therapeutic liposomes for targeted delivery to early-stage apoptotic cells. PUBLIC HEALTH RELEVANCE: We propose to test feasibility of developing a targeted liposomal formulation for two drugs proven to protect ischemic myocardium from lethal reperfusion injury through independent mechanisms. Drug-carrying liposomes will be decorated with human annexin V for targeting to phosphatidylserine exposed on the surface of cardiomyocites at the early stages of apoptosis. Intravenous administration of such liposomes immediately before the beginning of reperfusion could serve as an adjunct therapy for angioplasty and/or thrombolytic administration, which are the standard of care for patients with acute myocardial infarction.

心肌梗死是一种致残性疾病，梗死面积是死亡率的主要决定因素。为了限制梗死面积和改善功能恢复，必须对缺血心肌进行再灌注。然而，再灌注本身会对先前缺血的心肌造成不可逆的损伤。心脏损伤的一个重要部分是由在再灌注开始时立即开始的细胞凋亡引起的。因此，再灌注损伤被认为是治疗急性心肌梗死患者的重要新药理学靶点。我们建议开发两种药物的靶向脂质体制剂，证明通过独立的机制保护心肌。载药脂质体将修饰人膜联蛋白V，用于靶向在细胞凋亡早期暴露于心肌细胞表面的磷脂酰丝氨酸。在再灌注开始之前立即静脉内施用这种脂质体可以用作血管成形术和/或溶栓施用的辅助疗法，血管成形术和/或溶栓施用是心肌梗死患者的护理标准。所提出的策略的优点是：1）从再灌注的第一时刻开始，当凋亡仍然是可逆的时，在心肌细胞中递送非常显著量的药物，2）避免游离药物所必需的高剂量方案的副作用，以及3）通过独立机制起作用的两种药物的细胞内递送增加了成功治疗的可能性。将在心肌细胞的原代培养物中评价靶向载药脂质体。我们将建立早期凋亡细胞的内化机制，并评估膜联蛋白靶向载药脂质体的治疗潜力。将在小鼠心肌缺血/再灌注模型中研究脂质体的生物分布、靶向药物递送和体内保护作用。如果成功，所提出的策略将建立使用膜联蛋白靶向治疗脂质体作为心肌梗死辅助治疗的可行性。它还将推进开发治疗性脂质体的新技术，用于靶向递送到早期凋亡细胞。 公共卫生关系：我们建议测试开发两种药物的靶向脂质体制剂的可行性，这两种药物被证明通过独立的机制保护缺血心肌免受致死性再灌注损伤。载药脂质体将修饰人膜联蛋白V，用于靶向在细胞凋亡早期暴露于心肌细胞表面的磷脂酰丝氨酸。在再灌注开始之前立即静脉内施用这种脂质体可以用作血管成形术和/或溶栓施用的辅助疗法，血管成形术和/或溶栓施用是急性心肌梗死患者的护理标准。