Atherosclerotic cardiovascular disease results in close to 20 million deaths annually. The hallmark of the disease is the accumulation of plaques in the arterial wall. These plaques form when macrophages are subjected to lipid-rich environments which lead to their transformation into lipid-rich foam cells that can form artery clogging obstructions. In addition, sudden and unexpected rupture of these plaques can lead to sudden death through myocardial infarction and stroke. While recent advances in intravascular imaging, including magnetic resonance imaging (MRI), have aided in plaque identification, newer imaging and diagnostic modalities are required to monitor atherosclerotic plaque buildup in the arteries. ? ? Novel and proprietary gadolinium (Gd)-containing nanospheres developed by Luna Innovations (Trimetaspheres, TMS) provide a platform for developing superior new MRI contrast agents. Our overall hypothesis is that these atherosclerotic-targeting endohedrals (ATE or Gd3N@C80-derivatives) can be endocytosed by macrophage foam cells found in atherosclerotic lesions and thus be used as superior MRI contrast agents for plaque formation in patients with atherosclerosis. To test this hypothesis we will develop ATE that will be endocytosed by foam cells so plaques on arterial walls can be imaged using conventional MRI. Our long term goal is to develop commercially-feasible reagents that can be used to detect the in vivo formation of vulnerable atherosclerotic plaques and monitor the progression of the disease. Information obtained from these studies will be beneficial to physicians in their efforts to asses a patients atherosclerotic plaque profile and possibly to predict and prevent sudden MI induced by plaque disruption. ? ? To achieve our overall goal we propose the following specific aims: ? ? AIM 1: Synthesis and Characterization Gd3N@C80 Atherosclerotic-Targeting Endohedrals (ATE): 1) Functionalize Gd3N@C80 with cholesterol moieties for enhanced uptake into macrophage foam cells, 2) Develop formulations for """"""""active"""""""" and """"""""passive"""""""" Gd3N@C80-cholesterol molecules, 3) Characterize ATE considering solubility and MRI relaxivity parameters. ? ? AIM 2: Examine the cellular uptake of atherosclerotic-targeting endohedrals (ATE): Monitor and quantitate cellular uptake of the ATE by macrophages foam cells compared to other cell types. ? ? A profound need exists for more efficient, targeted, and safe biodistribution of contrast agents. With intravenous injection, current Gd chelates distribute throughout the body and are quickly excreted through the kidneys. These agents do not target specific sites; rather show vascular distribution and breakdown of normal barriers. The compounds developed here will begin to address these issues by identifying promising compounds in vitro that can be used to test for efficacy in mouse models of atherosclerosis in Phase II. ? ? ?
