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. Water comprises ~80% of most soft tissue. The contrast of proton MRI depends mainly on the density of the nucleus (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 development 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 (CLIO) nanoparticles and other iron oxide formulations affect T2 primarily and lead to decreased signals. On the other hand, the paramagnetic T1 agents, such as gadolinium (Gd3+), and manganese (Mn2+), accelerate T1 relaxation and lead to brighter contrast images.
The superparamagnetic iron oxide (SPIO) structure is composed of ferric iron (Fe3+) and ferrous iron (Fe2+). The iron oxide particles are coated with a protective layer of dextran or other polysaccharide. These particles have large combined magnetic moments or spins, which are randomly rotated in the absence of an applied magnetic field. SPIO is used mainly as a T2 contrast agent in MRI, though it can shorten both T1 and T2/T2* relaxation processes. SPIO particle uptake into the reticuloendothelial system (RES) is by endocytosis or phagocytosis. SPIO particles are also taken up by phagocytic cells such as monocytes, macrophages, and oligodendroglial cells. A variety of cells can be labeled with these particles for cell trafficking and tumor-specific imaging studies. SPIO agents are classified by their sizes with coating material (~20–3,500 nm in diameter) as large SPIO (LSPIO) nanoparticles, standard SPIO (SSPIO) nanoparticles, ultrasmall SPIO (USPIO) nanoparticles, and monocrystalline iron oxide nanoparticles (MION) (1).
USPIO is composed of iron nanoparticles of 4–6 nm diameter and the hydrodynamic diameter with dextran coating is 20–50 nm. USPIO nanoparticles have a long plasma half-life because of their small size. The blood pool half-life of plasma relaxation times is calculated to be ~24 h in humans (2) and 2 h in mice (3). Because of its long blood half-life, USPIO can be used as blood pool agent during the early phase of intravenous administration (4). In the late phase, USPIO is suitable for the evaluation of the RES in the body, particularly in lymph nodes (5).
E-selectin is found on the cell surface of endothelial cells (6, 7). It binds to sialy-Lewisx (a carbohydrate moiety) on the cell-surface of leukocytes. Tumor necrosis factor α (TNFα) and interleukin-1 (IL-1), released from inflammatory stimuli, upregulate E-selectin and other adhesion molecule expression on the vascular endothelial cells, which leads to leukocyte adhesion to the activated endothelium. E-selectin and other selectins are involved in arresting leukocytes on the endothelium. A sialy-Lewisx mimetic was conjugated to USPIO nanoparticles for non-invasive MRI of E-selectin expression on activated endothelial cells (8).