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Title: “Superparamagnetic Iron Oxide Nanoparticles for Early Detection of Calcific Aortic Valve Disease”

Committee: Joyce Y. Wong, PhD – BU BME (Advisor) Allison Dennis, PhD – BU BME (Chair) Tyrone Porter, PhD – BU ME Dimitrios Mitouras, PhD – Brigham and Women’s Hospital/Harvard Medical School, Department of Radiology Frederick Schoen, MD/PhD – Brigham and Women’s Hospital/Harvard Medical School, Departments of Pathology and Health Sciences and Technology

Abstract: Calcific Aortic Valve Disease (CAVD) is the most common acquired valvular disorder in developed countries, and is estimated to affect more than 5 million Americans. In its severe form, the disease results in hemodynamically significant aortic stenosis, which causes a variety of negative physiological impacts to patients. All told, the physiological consequences of the disease mean that the heart must work harder to pump blood throughout the body, causing the heart muscle to weaken and putting patients at a significantly greater risk of cardiovascular event. However, no clinical imaging method currently available has the ability to reliably detect early CAVD, necessarily delaying diagnosis until patients are symptomatic and the disease has progressed to its late stages. Despite the extensive cost, recovery time, and heightened risk of post-surgical complications to patients, surgical approaches are often the only option for patients with aortic stenosis due to late diagnosis of the condition. The lack of diagnostic imaging techniques capable of detecting and monitoring early-stage disease is a major unmet need in the development of new treatments of CAVD.

To address this problem, we have developed a novel contrast agent for MRI to aid in earlier detection of CAVD by using chemically modified and targeted superparamagnetic iron oxide nanoparticles (SPIONs) targeted to hydroxyapatite (HA). We have characterized the in vitro physiochemical and binding properties of these SPIONs as well as the selectivity of their targeted binding. We have also done work to optimize the binding and MRI contrast properties of the SPIONs. Finally, we have assessed the medically-relevant properties of the SPIONs, including their potential for toxicity and systemic effects and their binding to excised human aortic valve samples.

Our results show that these HA-targeted SPIONs can be successfully fabricated via a fairly simple reaction scheme, and that they bind selectively to HA even in the presence of serum proteins. We have also determined that the reaction scheme for the addition of the poly(ethylene glycol) (PEG) is of particular importance in optimizing the MRI contrast properties of the SPIONs. Having a hydrophilic group linking the PEG to the SPIONs yields particles with the highest contrast. Additional studies indicated that these SPIONs do not have cytotoxic properties, and that they are not expected to interfere systemically with bone homeostasis, as they neither inhibit nor encourage HA nucleation and formation. We have confirmed that these particles are able to cross an endothelial barrier, and to bind to HA subsequently. Finally, we have demonstrated targeted binding of SPIONs to sites of calcification in excised human aortic valve tissue. All together, these studies indicate that these HA-targeted SPIONs are suitable for further development as an MRI contrast agent for the early detection of CAVD.