Differential uptake of ferumoxtran‐10 and ferumoxytol, ultrasmall superparamagnetic iron oxide contrast agents in rabbit: Critical determinants of atherosclerotic plaque labeling

Abstract

To compare atherosclerotic plaque uptake of a first (ferumoxtran-10) and second generation (ferumoxytol) ultrasmall superparamagnetic iron oxide (USPIO) contrast agent with different pharmacokinetic/pharmacodynamic properties. New Zealand White rabbits maintained on a high cholesterol/fat diet were subjected to balloon injury to the abdominal aorta. Ferumoxtran-10 or ferumoxytol (500 micromol/kg) was administered at 2, 4, and 8 weeks following injury. In vivo magnetic resonance imaging (MRI) was performed immediately prior to, immediately after, and 6 days post-contrast administration. Ex vivo MRI, histologic, and inductively coupled plasma-mass spectrometry (ICP-MS) iron analyses were performed on the excised vessels. The blood pool clearance of ferumoxytol (t(1/2) < or = 6 hours) was more rapid than that of ferumoxtran-10 (t(1/2) < or = 48 hours). Decreased in vivo MRI signal intensity in the abdominal aorta was observed at 2, 4, and 8 weeks following injury with ferumoxtran-10, but not with ferumoxytol. Consistent with these observations, ex vivo MRI signal intensity was decreased in the ferumoxtran-10 vessels, and to a lesser degree in the ferumoxytol vs. control vessels (- contrast agent). In contrast, in vitro macrophage phagocytosis of USPIO was four to six fold greater with ferumoxytol than with ferumoxtran-10. Additionally, the absolute iron content correlated with ex vivo MRI signal intensity in all vessels (r = -0.86, P < 0.0001). These data suggest that the exposure period of atherosclerotic plaque to USPIO rather than the kinetics of the USPIO uptake by plaque alone is a critical criterion for experimental design of in vivo studies.