# Molecular Imaging with \({}^{68}\)Ga Radio-Nanomaterials: Shedding Light on Nanoparticles
## 4 Biomedical Applications of \({}^{68}\)Ga-Labeled Nanoparticles
### Iron Oxide Nanoparticles (IONPs)  
Iron oxide nanoparticles (IONPs) have been broadly used as imaging probes [82]. Their size-dependent MRI properties together with their superparamagnetic behavior, biocompatibility and chemical stability place them as a particularly important NP type for biomedical applications [83]. IONPs are typically composed of magnetite (Fe\({}_{3}\)O\({}_{4}\)) and/or maghemite (\(\gamma\)-Fe\({}_{2}\)O\({}_{3}\)) nanocrystals, which may exhibit different shapes (spheres, cubes, rods, rings, flowers, pyramids, etc.). Regarding coating molecules, the most commonly used ones are organic polymers, such as polyethylene glycol (PEG), oleic acid, dextran, chitosan, phospholipids, and other amphiphilic polymers. As tracers for molecular imaging, IONPs are most commonly used for MRI. Due to their superparamagnetic behavior they have been mainly used for T\({}_{2}\)-weighted MRI, therefore producing a darkening effect on the tissue surrounding them [84; 85; 86]. Nevertheless, several disease conditions, such as bleeding or calcifications, create an endogenous hypointense signal that makes IONPs indistinguishable from biological tissue. This drawback has focused research on finding methods for developing IONPs that serve as positive contrast agents for T\({}_{1}\)-weighted MRI. Studies have demonstrated that the downsizing of IONP core or coating thickness causes a shift on the NP magnetic behavior from superparamagnetic towards paramagnetic, thus creating T\({}_{1}\)-weighted MRI contrast agents [87; 88; 89; 72]. Additionally, IONPs are being used as a contrast agent in a novel technique that has gained strength in the research field during the past few years, Magnetic Particle Imaging (MPI) [90]. MPI can  
Figure 3: Different types of nanomaterials and the molecular imaging modalities to which they are applied. Ultrasound image adapted from [PERSON] et al. [69], nuclear imaging image adapted from [PERSON] et al. [79], Optical Imaging (OI) image adapted from [PERSON], [PERSON] et al. [80], Magnetic Particle Imaging(MPI) image adapted from [PERSON], [PERSON] et al. [81]. visualize superparamagnetic iron oxide (SPIO) tracers by direct induction, meaning MPI signal increases linearly with the amount of SPIO present in the imaged volume. Given this, MPI can be seen as a \"hotspot\" imaging technique with no background signal, similar to nuclear imaging techniques but without ionizing radiation. In addition, unlike OI, ultrasound, X-ray, and other imaging methods, its magnetic signal suffers zero attenuation with depth. However, the lack of anatomical information from this technique implies it cannot be used as a single imaging modality, again similarly to nuclear imaging techniques. This technique is still in its infancy; however, it has tremendous potential to surpass some of the limitations of IONPs in MRI without the inconvenience associated to nuclear imaging techniques. Several research groups have already demonstrated the capability of MPI to track stem cells in small-animal models systemically and longitudinally [81; 91; 92]; and to visualize brain and tumor vasculature for potential diagnosis of stroke and cancer, using SPIO nanoparticles [78; 93] (Figure 4). In addition to these single imaging modalities, IONPs have been reportedly used as probes for multimodal PET/MRI imaging. With the fusion of these two techniques PET imaging takes advantage of the excellent soft tissue contrast resolution and pathological discrimination offered by MRI, overcoming its lack of anatomical detail. To provide signal in PET, IONPs have been radiolabeled with different radioisotopes such as \({}^{64}\)Cu [5; 6; 7; 95], \({}^{68}\)Ga [70; 72; 96; 97; 98; 99], \({}^{18}\)F [2; 3; 4], \({}^{124}\)I [12; 13], \({}^{11}\)C [17], and \({}^{89}\)Zr [100]. IONP-based \({}^{68}\)Ga nanoradiotracers have been assessed in preclinical models to ensure biocompatibility and study in vivo biodistribution. [PERSON] et al.