Currently, there is no optimal medical therapy for peripheral vascular disease (PVD). A noninvasive method for detecting angiogenesis would provide invaluable information for managing PVD patients as well as for detecting response to angiogenic therapies. Cell adhesion integrins regulate angiogenesis by controlling the migration and invasion of vascular endothelial cells. In particular, the alpha(v)beta(3) integrin is ideally suited for detection of angiogenesis because only very low levels are expressed in normal vessels, expression quickly increases upon ischemia and it is expressed at higher density than other integrins. We have developed a novel, site-targeted, paramagnetic nanoparticle contrast agent for magnetic resonance imaging of molecular epitopes. The agent is a small (approximately 250 nm diameter), lipid-encapsulated, perfluorocarbon nanoparticle covalently coupled to an alpha(v)beta(3) specific antagonist. One key advantage of molecular imaging with this unique nanoparticle is the unusually large paramagnetic payload (approximately 90,000 Gd-DTPA complexes per nanoparticle) for high T1-weighted relaxivity. This provides a higher detection sensitivity and a better signal-to-noise ratio than previously achieved. The central hypothesis of this research is that alpha(v)beta(3)-targeted paramagnetic nanoparticles will allow sensitive detection of the early molecular signatures of angiogenesis. Accordingly, we have developed the following specific aims: 1) Develop and validate the following animal models of PVD to mimic a wide range of clinical conditions: femoral artery ligation, high-cholesterol diet, pro-angiogenic therapy and anti-angiogenic pharmacological manipulation. 2) Optimize molecular imaging techniques by quantifying gadolinium bound to angiogenic vasculature, modeling MRI signals, evaluating the sensitivity of different imaging sequences to gadolinium and developing automated unbiased image analysis programs. 3) Utilize alpha(v)beta(3)-targeted nanoparticles to demonstrate molecular imaging of angiogenesis in animal models developed in Aim 1. Apply mathematical models of tissue compartmentalization to determine the contributions of target binding and vascular permeability to MRI signal enhancement.
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