A Magnetic Resonance Iron Oxide Imaging Agent Targeting Activated GPIIb/IIIa on Platelets Allows In vivo Detection of Thrombosis and Monitoring of Thrombolysis

Abstract

Background: Platelets are the key to thrombus formation and play a major role in plaque rupture. Here, we evaluate theabilityof amagnetic resonance imaging (MRI) contrast agent consisting of microparticles of iron oxide (MPIO) and a single-chain antibody targeting ligandinduced binding sites (LIBS) on activated GPIIb/IIIa to image carotid artery thrombi. Methods and results: Anti-LIBS or control antibody were conjugated to 1 m-sized MPIOs (LIBS–MPIO/control–MPIO). Non-occlusive mural thrombi were induced in BL/6 mice using 6% ferricchloride. MRI (9.4 T) of the carotid artery was performed once before and repeatedly in 12min long sequences after LIBS–MPIO/control–MPIO injection. After 36min, a significant signal void, which is the typical effect of iron oxide-based contrast agents and which notably extends beyond the particle size, was observed with LIBS–MPIO, but not control–MPIO (P< 0.01) and corresponded to LIBS–MPIO binding as confirmed by histology. After thrombolysis, in LIBS–MPIO injectedmice the signal void subsided, indicating successful thrombolysis. On histology, MPIO-content of thrombus, as well as thrombus size, correlated significantly with LIBS–MPIO-induced signal void (both P< 0.01). Conclusions: We describe a novel approach for molecular imaging allowing in vivo targeting of magnetic resonance contrast agents to activated platelets. Thereby, thrombi canbedetectedwithexcellent resolutionandcontrast properties, which are suitable for coronary artery imaging in humans. Furthermore, success or failure of thrombolytic therapy can be monitored. This novel non-invasive technique provides rapid detection and quantification of thrombi, such as found in myocardial infarction, pulmonary embolism and on the surface of ruptured or rupture-prone atherosclerotic plaques.