2.1.2. Clinical Use and Further Perspectives Iron Oxide

Currently, Feraheme® (ferumoxytol) which is approved by the U.S. Food and Drug Administration (FDA) as well as in Europe and Canada is the most successful iron oxide-based drug. It is prescribed to patients with iron deficiency anemia and chronic kidney disease. It can be considered as a great advantage that iron is a naturally occurring element of the body which also leaves the body via natural pathways of iron metabolism [109]. Feraheme is based on non-stoichiometric magnetite MNPs with diameter (d) ~ 7 nm and hydrodynamic diameter (dH) = 28–33 nm coated with carboxy-dextran [66]. Feraheme is also an 'off label' magnetic resonance angiography (MRA) and magnetic resonance imaging (MRI) contrast agent [66,110]. In order to study MNP uptake by macrophages in vivo, high-resolution 3D-maps of pancreatic inflammation were generated using MRI and it showed that the MNP uptake by macrophages was higher in the inflamed pancreatic lesion in T1D-models [111]. Therefore, the special properties of the inflammatory setting on noninvasive imaging have to be considered. The capability of iron oxide to produce reactive oxygen species (ROS) was recently discovered to be usable in order to treat leukaemia [112]. In contrast to intravenously administrated drugs, the oral delivery (OD) is more popular with patients. Yet, the passage of the gastrointestinal (GI) tract, which has a very low pH level, [113] is a problem for iron oxides since they degrade at this pH. Thus, to overcome this limitation, a coating is required which is stable in the wide pH range of 2–8. Coatings such as gold or silica oxide are applicable for this purpose since these materials are stable in the GI tract.

Mesenchymal stem cells (MSC) have been demonstrated to be a promising tool for the treatment of many types of human diseases, including liver fibrosis and hepatocellular carcinoma (HCC) [114–118]. Labeling of MCS with MNPs can be used as a supplementary diagnostic approach. Recently, Faidah at al., proved that application of MNPs have not changed the viability and proliferative capabilities of MSCs in a rat cirrhosis model based on a carbon tetrachloride (CCl4) model for toxic liver injury [119]. Additionally, similar results by Lai and co-authors have shown that MSCs that overexpress human hepatocyte growth factor (HGF) promote liver recovery in a rat liver fibrosis model [120]. Further, labeling of MSC with NP led to an accumulation of the cells in MRI-based imaging [119,120], which seems to confirm the idea that magnetic NPs in liver fibrosis can be used as a diagnostic agent for MRI.

The off-label use of feraheme is continuing to grow. The assessment of the stage of liver fibrosis remains a key issue in patient diagnostics. Currently, the gold standard is still given by a liver biopsy while imaging techniques as elastography and relaxometry have not been elaborated in this regard, particularly, for proving moderate fibrosis [121]. A recent study showed that patients with different stages of liver fibrosis exhibited MRI-assessible differences. One should, however, be aware that T2 parameters can be quantified via a dual echo turbo-spin echo technique. Besides, these applications can also help to understand different stages of fibrosis patients [121]. It is noticeable that T2 or negative contrast agents possess superparamagnetic properties and are represented by nanoparticles with iron oxide core or other magnetic materials [122]. For this purpose, researchers are using different types of synthesis, shapes and covering of nanoparticles with magnetic cores. One should, nevertheless, consider the associated problems from another perspective: Li and coworkers proposed to conjugate Fe3O4 NPs with immunofluorescence markers (indocyanine green (ICG). Further, a targeting ligand for integrin avb3, arginine–glycine–aspartic acid (RGD) expressed by HSCs to detect early stages of liver fibrosis, was used [123]. A similar approach was used by Zhang and coauthors, who investigated diagnostic of liver fibrosis stages in a rat model induced by CCl4 injection. Although they were using molecular MRI with RGD peptide, modified ultrasmall superparamagnetic iron oxide nanoparticles (USPIO) were demonstrated to be a promising tool for noninvasive imaging of the progression of the liver fibrosis [124].

Furthermore, one should note that together with the advantageous properties of magnetic materials which makes them usable as MRI contrast agents, the iron overload in tissues can be really harmful. Thus, Wei and coauthors reported that a single dose of MNP application at a high concentration (5 mg Fe/kg) induced a septic shock response at 24 h and provoked high levels of serum markers (ALT, AST, cholesterol and other markers), which was noted within 14 days. Moreover, a high dose of MNPs activated significant expression changes of a distinct subset of genes in cirrhosis liver compared with a normal dose of MNP application (0.5 mg Fe/kg) [125]. Furthermore, Lunov et. al. analyzed the impact of MNPs on macrophages and demonstrated that overload of iron leads to apoptosis in these cells, which is mediated via activation of the c-Jun N-terminal kinase (JNK) pathway [126]. This investigation demonstrated that iron overload caused by MNP application may have dramatic effects, particularly on the liver, which contains a large numbers of macrophages.
