Reconstituted High-Density Lipoprotein Nanoparticles as Multi-modal Contrast Agents for Molecular Imaging of Atherosclerosis and Tumors.

摘要

Atherosclerosis is a chronic inflammatory disease initiated by modified lipoprotein deposits in the arterial vessels walls. The inflammatory response activated monocytes that take up modified lipoproteins. The activated monocytes then transformed to macrophages and foam cells, which may undergo apoptosis. Active macrophages also express metalloproteinases (MMPs), which degrade the extracellular matrix and make a thin fibrous cap. The progression of atherosclerosis may eventually cause plaque rupture and coronary artery disease, myocardial infarction, cerebrovascular disease, peripheral vascular disease, mesenteric ischemia and stroke if large thrombi block the arteries. Therefore, active inflammation with macrophage infiltration to vessel walls and a thin fibrous cap with a large lipid necrotic core are considered to be major indicators among several other factors (e.g. intraplaque hemorrhage and angiogenesis) for the high-risk plaques prone to rupture. The accurate non-invasive diagnosis of atherosclerosis is in urgent need. Molecular imaging of biological and pathological biomarkers in atherosclerosis is one of the promising solutions to advance diagnostic techniques. In this thesis, we developed high-density lipoprotein (HDL) nanoparticles as molecular magnetic resonance (MR) imaging probes for molecular imaging of atherosclerosis targeting macrophages and collagens, two major components playing central roles in the progression and regression of atherosclerosis. First, we demonstrated that incorporation of an apoE derived lipopeptide (P2A2) in HDL nanoparticles can enhance MR signal for imaging of macrophages in atherosclerosis as compared to unmodified HDL nanoparticles in apoE-/- mice. Second, we rerouted HDL nanoparticles from their natural macrophage target to collagens after functionalization with collagen-specific EP3533 peptides, which can then be used for non-invasive in vivo monitoring the regression of atherosclerotic plaques by MR in a Reversa mouse model. Third, we successfully targeted angiogenic endothelial cells using HDL nanoparticles by conjugating alphavbeta 3 integrin-specific cyclic 5-mer RGD peptides in a xenograft tumor mouse model with a multi-modal imaging approach by MR, near infrared fluorescence imaging, and confocal microscopy. Since atherosclerosis and tumor share the same the same alphavbeta3 integrin expression in angiogenesis, these nanoparticles has the potential for imaging angiogenesis in atherosclerosis.