Molecular Imaging of Angiogenesis in Early-Stage Atherosclerosis With α _v β ₃ -Integrin–Targeted Nanoparticles

Abstract

Background-Angiogenesis is a critical feature of plaque development in atherosclerosis and might play a key role in both the initiation and later rupture of plaques that lead to myocardial infarction and stroke. The precursory molecular or cellular events that initiate plaque growth and that ultimately contribute to plaque instability, however, cannot be detected directly with any current diagnostic modality. Methods and Results-Atherosclerosis was induced in New Zealand White rabbits fed 1% cholesterol for Ϸ80 days.␣ v ␤ 3 -Integrin-targeted, paramagnetic nanoparticles were injected intravenously and provided specific detection of the neovasculature within 2 hours by routine magnetic resonance imaging (MRI) at a clinically relevant field strength (1.5 T). Increased angiogenesis was detected as a 47Ϯ5% enhancement in MRI signal averaged throughout the abdominal aortic wall among rabbits that received ␣ v ␤ 3 -targeted, paramagnetic nanoparticles. Pretreatment of atherosclerotic rabbits with ␣ v ␤ 3 -targeted, nonparamagnetic nanoparticles competitively blocked specific contrast enhancement of the ␣ v ␤ 3 -targeted paramagnetic agent. MRI revealed a pattern of increased ␣ v ␤ 3 -integrin distribution within the atherosclerotic wall that was spatially heterogeneous along both transverse and longitudinal planes of the abdominal aorta. Histology and immunohistochemistry confirmed marked proliferation of angiogenic vessels within the aortic adventitia, coincident with prominent, neointimal proliferation among cholesterol-fed, atherosclerotic rabbits in comparison with sparse incidence of neovasculature in the control animals. Conclusions-This molecular imaging approach might provide a method for defining the burden and evolution of atherosclerosis in susceptible individuals as well as responsiveness of individual patients to antiatherosclerotic therapies.

Preparation and initial characterization of biodegradable particles containing gadolinium-DTPA contrast agent for enhanced MRI

“…The particles are spherically shaped, stable, and not agglomerated. The encapsulation of Gd-DTPA with this W/O/O protocol is similar to or higher than that shown with other encapsulation methods (18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Most importantly, the Gd-DTPA-loaded microparticles were shown to augment contrast in in vitro studies similarly to Gd-DTPA alone.…”

“…Faranesh and colleagues (18) demonstrated the utility of the inclusion of small amounts of Gd-DTPA in PLGA microparticles for tracking a drug delivery vehicle. Additionally, several groups have created gadolinium-containing micelles, microspheres, nanoparticles, and liposomes for the purposes of targeting delivery or modifying the biodistribution to increase the site-specific concentration of gadolinium over that of aqueous gadolinium or gadolinium directly conjugated to the targeting molecule (19)(20)(21)(22)(23)(24)(25)(26). Toward the same goals, this article details a method for the entrapment of hydrophilic agents, specifically Gd-DTPA, with very high loading in a polymeric particulate system as well as work toward achieving a targetable imaging agent particle formulation for the detection of staged atherosclerosis.…”

Endothelial α ν β 3 Integrin–Targeted Fumagillin Nanoparticles Inhibit Angiogenesis in Atherosclerosis

“…9 Subsequently, we have developed MRI and postprocessing techniques to permit molecular imaging of the diffuse proliferating neovasculature associated with atherosclerotic plaque development. 10,11 The widespread expression of ␣ ␤ 3 integrins observed by MR agreed with the diffuse nature of angiogenesis microscopically observed in the early atherosclerotic aortas of cholesterol-fed rabbits.The importance of angiogenesis in the progression of atherosclerotic plaque combined with the antiangiogenic impact of 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors, 12 suggests that suppression of vasa vasorum expansion could stabilize or reverse disease progression. Antiangiogenic agents have been shown to decrease both neovascular proliferation and plaque development in animal models of atherosclerosis when administered chronically at high dosages.…”

NMR Transversal Relaxivity of Suspensions of Lanthanide Oxide Nanoparticles

“…For lanthanide ion based contrast agents, this was realized in various ways and different materials have been proposed including: Gd-loaded apoferritin, which allows the visualization of hepatocytes when the number of Gd-complexes per cell is about 4 × 10 7 , 5 perfluorocarbon nanoparticles, which contain around 94 200 Gd 3+ ions per particle providing extremely high relaxivity per particle and which have been already successfully used in molecular imaging of angiogenesis. [6][7][8][9][10] Alternatively, this may be achieved with superparamagnetic (SPM) particles, single domain ferromagnets possessing a very high magnetic moment (around 10 4 µ B ). 11,12 SPM particles have a much smaller effect on the T 1 water proton relaxation time than on the T 2 .…”