Fellowship in Support of Molly Wasserman entitled, "Synthetically Engineered Targeted Gold Nanoparticles for the Prevention of Restenosis Following Vascular Interventions"

HYPOTHESIS AND SPECIFIC AIM Atherosclerosis is the leading cause of death and disability in the Unites States.1 One out of every three deaths in the U.S. is directly attributed to cardiovascular disease, and this results in an average of one death every 40 seconds in the U.S.1 With an aging population, the anticipated prevalence of atherosclerotic coronary artery disease (CAD) and peripheral arterial disease (PAD) will continue to increase. Current surgical therapies for the treatment of severe CAD and PAD include percutaneous balloon angioplasty, percutaneous stenting, surgical endarterectomy, and surgical bypass grafting. However, the long-term durability of these therapies is suboptimal, often necessitating repeat interventions or surgery, or resulting in heart attack, stroke, or limb loss. The high failure rates are attributed to arterial remodeling and neointimal hyperplasia leading to arterial restenosis.2,3 Thus, there is clearly a need for new technology that will enable safe revascularization of diseased arteries while minimizing patient exposure to long-term risks. The objective of this project is to develop a highly innovative and targeted therapeutic to prevent restenosis following vascular intervention. Specifically, we aim to evaluate a novel nanoparticle that, when administered systemically, is capable of honing to the site of vascular injury and delivering small molecule therapeutics directly to the site of vascular injury with the goal of abrogating the formation of neointimal hyperplasia and restenosis. Our hypothesis is that systemic administration of our novel targeted nanoparticle will target to the site of arterial injury. To evaluate this hypothesis, we propose the following two aims for this 1-year proposal: Aim 1 – To synthesize and characterize a novel targeted gold nanoparticle (AuNP). Specifically, a targeted AuNP will be synthesized via addition of a thiol-terminated (-SH) ligand where upon the end opposite the thiol group contains a unique collagen binding peptide (CBP) sequence with an intervening polyethylene glycol (PEG) spacer (HS-PEG-CBP). An additional fluorophore ligand, rhodamine (Rhod), will be mixed as HS-PEG-Rhod with HS-PEG-CBP to allow nanoparticle visualization and manipulation of CBP ligand binding to the surface of the AuNP. Characterization will be performed via dynamic light scattering, zeta potential measurements (surface charge), and transmission electron microscopy imaging. Aim 2 – To evaluate intravascular binding of the novel targeted AuNP in vivo. We will perform the rat carotid artery balloon injury model of vascular injury followed by immediate tail vein injection of the targeted AuNP. Binding specificity to the site of arterial injury will be assessed using In-Vivo Imaging Systems (IVIS)® of whole arteries and organs and fluorescent histological imaging of artery and organ cross sections. Binding specificity will be assessed at multiple time-points between 2 hours and 2 weeks. RELEVANCE Atherosclerotic arterial vascular disease is the leading cause of death and disability in the U.S.1 Inpatient cardiovascular interventions to manage this burden are on the rise, with a 28% increase in the total number of procedures performed from 2000 to 2013.1 Unfortunately, these procedures are subject to high failure rates secondary to restenosis from neointimal hyperplasia, leading to significant patient morbidity and mortality.4-6 Over the past several decades, the only therapy that has directly affected restenosis rates following cardiovascular intervention