We have shown that modified human ferritin nanoparticles can image vascular macrophages in vivo in murine carotid arteries through fluorescence or MRI. Thus, an intrinsic cage-like human protein can be used for in vivo macrophage and vascular imaging.
Previous animal and human studies have shown an increase in ferritin in atherosclerotic plaques, mainly in macrophages, and association with plaque rupture[22
]. Increased ferritin in atherosclerotic lesions has also been associated with pro-inflammatory cytokines and atheroma cell apoptosis[22
]. The heavy (H) subunit of ferritin is generally believed to play a key role in iron transport[29
] and several investigators have also found evidence for receptor-mediated uptake of ferritin, especially the H subunit studied here, by inflammatory and other cell types[25
]. While we and others have previously shown good uptake of modified HFn in macrophages in vitro[19
], the full mechanisms for increased ferritin accumulation in macrophages in vivo
, particularly in human atherosclerotic lesions, are not fully understood. The important finding in this study is that HFn accumulates in vascular macrophages in vivo
and may serve as an intrinsic macrophage imaging agent without additional macrophage targeting moieties.
A number of molecular imaging strategies have been developed for detecting macrophages in atherosclerosis, such as MRI[5
], fluorescence imaging[7
], and nuclear imaging (PET and SPECT)[9
]. In our study, fluorescence imaging had insufficient signal penetration to allow fully noninvasive detection, requiring in situ
carotid exposure. A more sensitive fluorescence imaging technique, such as fluorescence molecular tomography, may allow fully noninvasive imaging[37
]. MRI allowed noninvasive detection, but relies on T2* signal loss, which can be challenging. The application of “positive contrast” methods to high-field small-animal MRI systems for iron detection may be advantageous[6
While HFn has the advantage of being a modified human protein, the clinical translation of this approach from a short-term animal model to the chronic, complex human disease certainly requires further study. The cage-like structure of HFn also makes it a highly adaptable platform for imparting targeting and therapeutic capabilities to optimize further its “theranostic” potential[18