Imaging of Oxidation-Specific Epitopes in Atherosclerosis and Macrophage-Rich Vulnerable Plaques

Oxidative stress, and in particular oxidation of lipoproteins, is a hallmark of atherosclerosis. Upon entry of lipoproteins into the vessel wall, a cascade of pro-atherogenic pathways is initiated whereby the reaction of reactive oxygen species with substrates amenable to oxidation, such as polyunsaturated fatty acids, generates a variety of oxidation-specific epitopes on lipoproteins, proteins in the vessel wall, and apoptotic macrophages. Several of these oxidation-specific epitopes have been well characterized and specific murine and fully human antibodies have been generated in our laboratory to detect them in the vessel wall. We have developed radionuclide, gadolinium and iron oxide based MRI techniques to noninvasively image oxidation-specific epitopes in atherosclerotic lesions. These approaches quantitate plaque burden and also allow detection of atherosclerosis regression and plaque stabilization. In particular, gadolinium micelles or lipid-coated ultrasmall superparamagnetic iron oxide particles containing oxidation-specific antibodies accumulate within macrophages in the artery wall, suggesting they may image the most unstable plaques. Translation of these approaches to humans may allow a sensitive technique to image and monitor high-risk atherosclerotic lesions and may guide optimal therapeutic interventions

Degradation, Metabolism and Relaxation Properties of Iron Oxide Particles for Magnetic Resonance Imaging

Whereas the effect of size and coating material on the pharmacokinetics and biodistribution of iron oxide based contrast agents are well documented, the effect of these parameters on liver metabolism has never been investigated. The primary purpose of this work was to evaluate the effect of iron oxide particle size and coating on the rate of liver clearance and particle degradation using a rat model. The magnetic and relaxation properties of five different iron oxide contrast agents were determined prior to the onset of the animal studies. The R2* values and the T1-enhancing efficacy of the agents were also evaluated in blood using phantom models. The results of these studies indicated that the efficacy of these agents was matrix and frequency dependent. Correlations between the R2* values and the magnetic properties of the agents were established and a new parameter, Msat/r1, was created to enable better estimations of contrast agent T1-enhancing efficacy in blood. The bio-distribution of one of the agents was also evaluated to assess the importance of sub-cellular particle distribution, using an isolated rat liver cell model. Phantom models were also used to verify that materials with magnetic properties similar to the particle breakdown products (ferritin/hemosiderin) may induce signal reduction when compartmentalized in a liver cell suspension. The results revealed that the cellular distribution of the agent did not influence the rate of particle degradation. This finding conflicted with current theory. Additionally, the study indicated that the compartmentalization of magnetic materials similar to ferritin may induce significant signal loss. Methods enabling the accurate determination of contrast agent concentration in the liver were developed and validated using one of the agents. From these measurements the liver half-life of the agent was estimated and compared to the rate of liver clearance, as determined from the evolution of the effective transverse relaxation rate (R2*) in rat liver. The results indicate that the liver R2* enhancement persisted at time points when the concentration of contrast agent present in the liver was below method detection limits. The prolonged R2* enhancement was believed to be a result of the compartmentalisation of the particle breakdown products within the liver cells. Finally, the liver clearance and degradation rates of the five different iron oxide particles in rat liver were evaluated. The results revealed that for materials with similar iron oxide cores and particle sizes, the rate of liver clearance was affected by the coating material present. Materials with similar coating, but different sizes, exhibited similar rates of liver clearance. In conclusion, the results of this work strongly suggest that coating material of the iron oxide particles may contribute significantly to the rate of iron oxide particle clearance and degradation in rat liver cells

Fractionated Feridex and positive contrast: in vivo MR imaging of atherosclerosis.

International audienceMacrophages have been identified as a critical factor in the pathogenesis of atherosclerosis. Ultrasmall iron oxide particles (USPIOs) have been used to passively target intraplaque macrophages. For dextran-based USPIOs, uptake into macrophages may be modulated by particle size. The aim of the current study was to test the efficacy of fractionated Feridex with respect to macrophage uptake in atherosclerotic rabbits. Fractionation of Feridex resulted in a 15-nm USPIO that exhibited a blood half-life of 15.9 h and liver retention of 6.4%. Blood clearance and liver retention of Feridex was 0.46 h and 60%, following administration of 4.8 mg Fe/kg Feridex. Atherosclerotic rabbits were administered 0.5 or 4.8 mg Fe/kg dosages of either fractionated Feridex or Feridex. MRI was performed at 1.5T over a 24-h time period postinjection. Perls and RAM-11 staining was performed to identify iron deposition. MRI showed a dose-dependent signal loss using conventional gradient echo (GRE) sequences following administration of fractionated Feridex. Even at low dose, significant signal loss was observed that correlated with histology. No signal attenuation or iron deposition was observed in the vessel wall of rabbits administered Feridex. Results of this study suggest that it may be possible to optimize USPIOs for intraplaque macrophage detection