New methods to deliver therapeutic drugs in myocardial ischemia/reperfusion injur

描述（由申请人提供）：保护心肌细胞免于死亡是降低心肌梗死（MI）相关死亡率的最佳方法。心肌梗死是由缺血/再灌注损伤（IR）引起的。IR引起肌细胞的生化和结构组成的许多有害变化，包括高能磷酸盐（ATP）的快速减少、肌细胞细胞骨架的不稳定和/或损伤以及进行性线粒体损伤。氧自由基（ODFR）在缺血再灌注损伤中起重要作用。再灌注导致额外的肌细胞坏死，这进一步增加了与MI相关的发病率和死亡率。在过去的20年中，许多药物，包括自由基清除剂，腺苷和钠-氢交换抑制剂，在动物模型中显示出减少或抑制坏死的前景，已在人体试验中进行了尝试，但尚未证明对改善发病率或死亡率有益。抗缺血化合物的临床试验可能失败的原因包括：1）强效药物不能达到有效浓度而不引起全身副作用/毒性;和/或2）不能在肌细胞处达到药物的有效浓度。为了真正了解抗缺血药物是否在减少梗死面积方面具有显著的益处，需要在正确的时间以有效浓度递送;在再灌注开始时。纳米技术的迅速发展使得能够设计新的运载工具，将毒品贩运到行动最有效的特定地区。在这种高度互动和集成的应用中，我们建议设计和开发一种新的和独特的递送载体，使用最先进的制药技术，能够将治疗药物递送到酸中毒组织。将药物递送至酸中毒组织将允许在整个再灌注期间将过氧化氢酶快速且持续地递送至心肌。在这些初步研究中，我们将使用内源性抗氧化蛋白过氧化氢酶。除了表征和优化过氧化氢酶颗粒向心室肌细胞的递送之外，我们将使用IR的体外和体内模型系统来测试递送的过氧化氢酶抑制肌细胞死亡的能力。如果我们成功，这种新的载体将为抗氧化剂药物提供新的机会，并刺激新的治疗剂的开发，这些治疗剂被选择性地设计成靶向IR损伤的许多区域，以及心肌梗塞的其他方面。 公共卫生相关性：如果可以实现，这种药物递送载体可以在现场或急诊室给予患有发展中的心脏病发作（即发展中的心肌梗死）的患者，并直接减少由事件引起的细胞死亡。心肌梗死后发病率和死亡率的最佳预测指标是死亡的心脏组织数量。因此，如果药物减少了细胞死亡的数量，它将直接降低发病率，死亡率以及患者和整个医疗保健系统的成本。此外，我们的递送载体不限于使用单一药物。在这些初步研究中，我们将使用容易获得的，充分表征的抗氧化剂过氧化氢酶。然而，递送载体将适用于许多其他自由基清除剂以及可以被设计为直接减少或防止肌细胞死亡的其他药物。这种药物输送载体的最终结果可能对美国的医疗保健系统产生重大影响。

DESCRIPTION (provided by applicant):: Protecting myocytes from death is the best way to lower the mortality associated with myocardial infarction (MI). MI results from ischemia/reperfusion injury (IR). IR causes many detrimental changes in the biochemical and structural composition of myocytes including a rapid decrease in high-energy phosphate (ATP), destabilization and/or damage to the myocyte cytoskeleton, and progressive mitochondrial damage. It has been established that oxygen-derived free radicals (ODFR) play an important role in the overall injury associated with IR especially during the reperfusion phase. Reperfusion results in additional myocyte necrosis, which further increases the morbidity and mortality associated with MI. Over the past 20 years many drugs, including free radical scavengers, adenosine, and sodium-hydrogen exchange inhibitors, which have showed promise in animal models in reducing or inhibiting necrosis have been tried in human trials but have not proven to be beneficial in improving morbidity or mortality. Among the reasons that clinical trials of anti-ischemic compounds may have failed include: 1) the inability of potent drugs to reach effective concentrations without causing systemic side effects/toxicity; and/or 2) the inability to achieve effective concentrations of the drug at the myocyte. To truly know whether anti-ischemic drugs have a significant benefit in reducing infarct size requires delivery at an effective concentration at the correct time; at the start of reperfusion. The rapid development of nanotechnology has allowed the design of new delivery vehicles capable of trafficking drugs to specific areas where the action is most effective. In this highly interactive and integrated application, we propose to design and develop a new and unique delivery vehicle using state of the art pharmaceutical techniques capable of delivering therapeutic drugs to acidotic tissue. Delivering the drug to the acidotic tissue will allow rapid and sustained delivery of catalase to the myocardium throughout the reperfusion period. In these initial studies, we will use the endogenous anti-oxidant protein catalase. In addition to characterizing and optimizing the delivery of catalase-particles to ventricular myocytes, we will test the ability of delivered catalase to inhibit myocyte cell death using both in vitro and in vivo model systems of IR. If we are successful, this new vehicle would provide renewed opportunities for antioxidant drugs as well as stimulate the development of new therapeutic agents selectively designed to target many areas of IR injury as well as other aspects of myocardial infarction. PUBLIC HEALTH RELEVANCE: If achievable, this drug delivery vehicle could be given to a patient with a developing heart attack (i.e. a developing myocardial infarct) in the field or in the emergency department and directly reduce the cell death resulting from the event. The best predictor of morbidity and mortality subsequent to myocardial infarction is the amount of heart tissue that dies. Therefore, if the drug reduces the amount of cell death, it will directly reduce morbidity, mortality, and the cost to the patient and the overall health care system. Furthermore, our delivery vehicle is not restricted to the use of a single drug. In these initial studies we will use the readily available, well-characterized antioxidant catalase. However, the delivery vehicle would be adaptable to many other free radical scavengers as well other drugs that could be designed to directly reduce or prevent myocyte cell death. The ultimate outcome of such a drug delivery vehicle could have a large impact on the health care system in the United States.