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.

Public Health Service Relevance Statement Significance: 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.