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Figure 2.3 (a) CT lymphography demonstrated a sentinel node (arrow). (b) The corresponding node was identified on T_2*‐weighted axial MR imaging (arrow). The node showed high signal intensity before the administration of superparamagnetic iron oxide (SPIO). (c) After the administration of SPIO, the node showed no SPIO enhancement and was diagnosed as malignant (arrow). (d) Histologic findings confirmed it as malignant. This node was almost entirely replaced by metastatic tissue (arrowheads).

      Source: Reproduced with permission from Motomura et al. (2011). Copyright © 2011, Springer Nature. DOI‐https://doi.org/10.1245/s10434‐011‐1710‐7.

The development of these applications led to the approval of the first MNPs that were used as contrast agents (Feridex and Resovist, see Table 2.1) in Europe and USA. In the organs not associated with MPS, or in the case of MNPs that are functionalized such as they escape the MPS, the Enhanced Permeability and Retention effect (EPR) in solid tumors plays an important role in their penetration into tumor tissue. Moreover, due to the lack of functional lymphatic vessels in malign tumors, the MNPs can accumulate in these tumors. This accumulation can be visualized in dark contrast images (Jain and Stylianopoulos 2010). Another approach for increasing the accumulation of MNPs in tumor tissues is to functionalize them with ligands targeting tumor markers like vascular or epithelial growth factors, α_vβ₃ integrins expressed by the endothelial cells in tumor vessels, folate receptors, and transferrin receptors. Apart from their use as CAs for tumor detection, MNPs in conjunction with MRI were used in MR angiography for the detection of cardiovascular diseases, vascular abnormalities, and inflammations (Nahrendorf et al. 2008).

Another important application of MNPs in MRI is the monitoring of cell therapies by cell tracking. In order to generate high‐contrast MRI images, the tracked cells are loaded with MNPs. Large numbers of MNPs can be loaded into the cells by electroporation, magnetofection, or cell‐penetrating peptides. In this manner, single cell detection can be achieved in vitro. Moreover, recent studies showed that the MNPs accumulate in lysosomes without affecting the cell functions (Ou et al. 2020). Several studies have shown that the delivery of antigen‐specific cytotoxic T‐lymphocyte, natural killer cells, and dendritic cells to the tumor or regional lymph nodes, could be monitored in vivo in real time (de Vries et al. 2005). Another important advantage of this type of approach is the possibility to monitor and to identify individuals who do not respond to the therapy. Other important applications of the combined use of MNPs and MRI are based on the observation that the MNPs could be taken up by monocytes and macrophages involved in the inflammation response; this provides information in different pathological processes such as atherosclerosis, pancreatic islet inflammation, or cardiac allograft rejection (Tong et al. 2019).

      The development of a nanoplatform able to create dual T₁ − T₂ contrast agents would represent a great advancement for medical applications of MNPs. This implies to create a CA with a high r₁ but, in the same time, with a low ratio r₂/r₁ (close to 1) (Blanco‐Andujar et al. 2016). Several strategies have been tested so far: doping the MNPs with T₁ ions, attaching T₁ ions on the surface of MNPs, and elaboration of core‐shell nanostructures having a r₂/r₁ ratio close to 1 but with the cost of a low r₂ (Xiao et al. 2014). Core@shell structures led to MNPs with higher r₂ values, especially if the distance between the core and the shell is increased by adding a nonmagnetic layer (SiO₂). Recent studies show that, in a case of a dual core@shell nanostructure, by increasing the thickness of the nonmagnetic layer, the r₂/r₁ ratio decreased. Very interestingly, the r₂ was quite high, reaching a value of 312 m M⁻¹ s⁻¹ (Yang et al. 2015a). This finding demonstrates the huge potential of these nanostructures in MRI applications.

      2.2.2 Magnetic Particle Imaging (MPI)

      MRI cell‐tracking applications and inflammation response characterization by using MNPs might be replaced soon by a novel emerging technique called Magnetic Particle Imaging (MPI) (Gleich and Weizenecker 2005). As it was stated before, the use of MNPs in MRI does have several drawbacks worth mentioning. Arguably, the most relevant is their rapid elimination from the bloodstream by MPS, hampering their use as more specific targeting agents. The negative contrast they produce is often masking the underlying anatomical tissue structure. Concurrently, the presence of different endogenous sources of contrast such as hemorrhage, air tissue interfaces, and magnetic field imperfections may lead to artefactual images. Because the contrast is produced by the change in the relaxation time of the protons, which in turn is inextricably connected to MNPs concentration, a reliable quantification of their concentration is difficult. Some of these restrictions are eliminated in MPI.

The MPI is based on the principle that MNPs that are magnetized by an external magnetic field can exhibit a nonlinear response in a near‐zero external magnetic field. When the MNPs are placed in an external magnetic field, the magnetization will follow it until a positive or negative saturation value is reached. In a basic MPI scanner setup, the structure of the static magnetic field is such that there is only 1 point in the 3D space where the magnetic field is zero. This point is called “field‐free point” (FFP). When, apart from the static magnetic gradient field, another AC magnetic field (in the range of few kHz) is created, only the MNPs situated in the FFP will follow the oscillations of the AC magnetic field. As such, only these MNPs can induce an electric current in a pick‐up coil. Moreover, due to the nonlinear dependence of the magnetization on the magnetic field strength (which usually is a Langevin function type dependence), the induced current will consist not only in the fundamental frequency of the applied AC magnetic field but also in multiples of the fundamental frequency (harmonics). By measuring the third harmonic, one may separate the contribution of paramagnetic ions or impurities to the induced current. This is possible because the paramagnetic response is linear and contains only the fundamental frequency. Following the spatial reconstruction of the