Magnetic resonance imaging (MRI) maps information about tissues spatially and functionally. Protons (hydrogen nuclei) are widely used to create images because of their abundance in water molecules, which comprise >80% of most soft tissues. The contrast of proton MRI images depends mainly on the nuclear density (proton spins), the relaxation times of the nuclear magnetization (T1, longitudinal; T2, transverse), the magnetic environment of the tissues, and the blood flow to the tissues. However, insufficient contrast between normal and diseased tissues requires the use of contrast agents. Most contrast agents affect the T1 and T2 relaxation times of the surrounding nuclei, mainly the protons of water. T2* is the spin–spin relaxation time composed of variations from molecular interactions and intrinsic magnetic heterogeneities of tissues in the magnetic field (1). Cross-linked iron oxide nanoparticles and other iron oxide formulations affect T2 primarily and lead to a decreased signal. On the other hand, paramagnetic T1 agents, such as gadolinium (Gd3+) and manganese (Mn2+), accelerate T1 relaxation and lead to brighter contrast images.
Endothelial cells are important cells in inflammatory responses (2, 3). Bacterial lipopolysaccharides, viruses, inflammation, and tissue injury increase secretion of tumor necrosis factor α (TNFα), interleukin-1 (IL-1), and other cytokines and chemokines. Emigration of leukocytes from blood is dependent on their ability to adhere to endothelial cell surfaces. Inflammatory mediators and cytokines induce chemokine secretion from endothelial cells and other vascular cells and increase their expression of cell-surface adhesion molecules, such as intracellular adhesion molecule-1, vascular cell adhesion molecule-1, integrins, and selectins. Chemokines are chemotactic to inflammatory cells (such as leukocytes and macrophages) attracting them to sites of inflammation and tissue injury. Under atherogenic conditions, deposition of lipids on the endothelial cell surfaces of the aorta and inflammatory cells leads to the development of atherosclerotic plaques (4), which may erode and rupture.
Ferritin (Fn) is composed of 12 or 24 subunits of heavy and/or light chains, which self-assemble to form a cagelike nanoparticle (nanocage) at physiological pH (7.4) with internal and external diameters of 8 nm and 12 nm for the 24 subunit Fn (5-7), respectively. There are four or eight ion channels for directing Fe2+ ions to multiple Fe2+/O oxidoreductase (“ferroxidase”) sites in the heavy chains for Fe2O3•H2O deposition in the Fn cavity. The ion channels also control reduction, dissolution, and exit of Fe2+ from the mineral with gated pores on the surface of Fn cages. Fe2+ ions are required for protein cofactor synthesis and anti-oxidant activity after stress. Most ferritins are intracellular and tissue-specific. For applications, the outer surface of Fn can be chemically or genetically modified with ligands, and the cavity of Fn can capture metal ions with high affinity (8). Uchida et al. (9) loaded iron oxide into the cavities of human heavy chain Fn (Fn-Fe) nanocages to study the in vitro uptake of Fn-Fe nanocages by macrophages. Fn-Fe nanocages have been studied for MRI of vascular macrophages in atherosclerotic plaques in mice (10).