Non-Invasive Imaging of Early Venous Thrombosis by 19F MRI Using Targeted Perfluorocarbon Nanoemulsions
Background—Non-invasive detection of deep venous thrombi and subsequent pulmonary thromboembolism are serious medical challenges and are difficult to detect by conventional ultrasound techniques.
Methods and Results—Here we report a novel technique for the sensitive and specific identification of developing thrombi making use of background free 19F MRI together with α2-antiplasmin peptide (α2AP) targeted perfluorocarbon nanoemulsions (PFCs) as contrast agent, which is cross-linked to fibrin by active factor XIII. Ligand functionality was ensured by mild coupling conditions using sterol-based post-insertion (SPIT). Developing thrombi with a diameter smaller than 0.8 mm could be unequivocally visualized in the murine vena cava inferior as hot spots in vivo by simultaneous acquisition of anatomical matching 1H and 19F MR images at 9.4 T with both excellent signal- and contrast-to-noise ratio (71±22 and 17±5, respectively). Furthermore, α2AP-PFC could be successfully applied for diagnosis of experimentally induced pulmonary thromboembolism. In line with the reported half-life of FXIIIa, application of α2AP-PFCs later than 60 min after thrombus induction did not any longer result in detectable 19F MRI signals. Corresponding results were obtained in ex vivo generated human clots. Thus, α2AP-PFCs can visualize freshly developed thrombi which might still be susceptible to pharmacologic intervention.
Conclusions—Our results demonstrate that 1H/19F MRI together with α2AP-PFCs is a sensitive non-invasive technique for the diagnosis of acute deep venous thrombi and pulmonary thromboemboli. Furthermore, ligand coupling by SPIT represents a unique platform for specific targeting of PFCs for in vivo 19F MRI.
- Received May 3, 2014.
- Revision received February 4, 2015.
- Accepted February 13, 2015.