Selective delivery of superoxide dismutase and catalase for restenosis prevention

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Cardiovascular disease (CVD) is the leading cause of death in the United States. CVD often stems from the development of atherosclerosis. Severe atherosclerosis requires surgical revascularization procedures to widen the vessel and restore blood flow. However, revascularization procedures often fail due to neointimal hyperplasia (NH). After revascularization there is an increased and localized over production of reactive oxygen species in the vessel wall. This pro-oxidant loss of redox homeostasis leads to an exacerbated proliferation, and migration of vascular smooth muscle cells (VSMC) towards the inner vessel wall, thereby causing NH. NH limits the successful outcomes of vascular interventions. Localized treatment with antioxidants, like the antioxidant enzymes superoxide dismutase and catalase, successfully reduces the rates of NH in a rabbit arterial injury model. In humans, localized treatment is rarely an option given the inaccessibility of full diseased vessels, leaving us with the option of systemic delivery. However, systemic delivery of antioxidants, fail to reach the necessary concentration at the site of interest underscoring the need for an approach that can be delivered systemically and can target the site of interest without the need of an accessible site. Macrophages are excellent candidates for antioxidant delivery to sites of inflammation, such as the site of arterial intervention, where they are naturally recruited to. Moreover, macrophages do deliver NP cargo to sites of inflammation. Therefore, the objective of this application is to determine the effectiveness of selective macrophage-mediated antioxidant enzyme delivery to the site of vascular intervention for prevention of NH. I hypothesize that macrophages will deliver antioxidant enzymes to the site of intervention, restoring redox homeostasis and inhibiting NH. To test this innovative hypothesis, I will obtain macrophages that will be loaded ex vivo with protected antioxidant enzymes in the form of nanoparticles for treatment of rats undergoing arterial surgery. Aim 1 will focus on the antioxidant enzyme nanoformulation and characterization, their interaction with macrophages; and will also interrogate the effects of antioxidant enzymes loaded macrophages on vascular cells in vitro. Aim 2 will interrogate the effect of antioxidant enzymes loaded macrophages on NH in vivo, using a novel unbiased 3D method to assess vascular injury. Successful completion of this project will elucidate whether selective antioxidant enzyme treatment inhibits NH; as well as establish a new approach for selective delivery of therapeutics to damaged sites in the vasculature. I, Ana Cartaya, will conduct the experiments outlined in this proposal in Dr. Edward Bahnson’s lab at the University of North Carolina-Chapel Hill (UNC-CH). Alongside Dr. Bahnson, Dr. Batrakova will serve as my co-sponsor during the course of my training. Dr. Batrakova is an associate professor and professor of Pharmacy at UNC- CH, and a close collaborator. My co-sponsors and I have together designed a training plan that will widen my research prowess and professional development. Upon completion of this proposal I will be positioned to undertake any competitive postdoctoral fellowship position at a research-intensive or governmental institution.