Iron-oxide nanoparticles have been used extensively to image hepatic and lymph node metastases in humans, and have an extensive safety record [42
]. Targeted iron-oxide nanoparticles have yet to be tested in humans, although no preclinical evidence of toxicity has been reported with these agents. Initial human data with a targeted Gd-based probe have now been obtained [10••
]. The fibrin-detecting gadolinium chelate, EP-2104R, has to date been given to 52 patients, with excellent short-term safety results [10••
]. However, concerns regarding the long-term accumulation of targeted Gd-based probes will need to be addressed, particularly in the case of Gd-based nanoparticles and micelles.
One of the advantages of larger constructs such as liposomes, however, is their potential to carry a therapeutic payload. Winter and colleagues [6
] have shown that a Gd-loaded liposome can be targeted to the αV
integrin, involved in plaque angiogenesis. Incorporating the anti-angiogenic agent fumagillin into the liposome reduced angiogenesis and subsequent uptake of the probe [43••
]. Recent data from Mulder and colleagues (presented, Society for Molecular Imaging 2008) also suggest that liposomes loaded with corticosteroids can significantly reduce plaque inflammation. These constructs thus facilitate a theranostic (therapeutic and diagnostic) approach, in which molecular imaging is performed not only to diagnose disease, but also to follow and monitor therapy.
The breadth and comprehensive nature of MRI are amongst its most appealing attributes. Nevertheless, multimodality MRI strategies are being developed and hold great promise. The Weissleder group [44••
] has conjugated 64
Cu to a magnetofluorescent nanoparticle to yield a PET-, fluorescence-, and magnetic resonance–detectable probe. Uptake of this multimodal nanoparticle by plaque macrophages in the aortic roots of ApoE−/−
mice could be imaged in vivo with both MRI and PET [44••
]. Moreover, the PET signal generated by this agent was significantly stronger than that generated by 18
FDG. Integrated magnetic resonance–PET systems have been constructed, and it is likely that such systems will play an important role in the clinical translation of molecular imaging.
Targeted molecular MRI of atherosclerosis is already playing an important role in basic science investigation, and the development and testing of novel pharmaceuticals. Although the clinical translation of these techniques holds much promise, safety, regulatory, and economic hurdles will need to be addressed. The recent human experience with EP-2104R is in many ways encouraging, and it is likely that additional selected agents will move into clinical trials. Further advances in the molecular imaging of atherosclerotic plaque will also be significantly facilitated by advances in therapy, specifically additional data showing the long-term safety of drug-eluting stents. The optimal approach to prevent cardiovascular events remains an area of significant debate and activity. It is unlikely, however, that a genomic- and biomarker-based approach alone will suffice, and complementary information provided by imaging techniques such as molecular MRI will thus be crucial.