# Molecular Imaging with \({}^{68}\)Ga Radio-Nanomaterials: Shedding Light on Nanoparticles
## 4 Biomedical Applications of \({}^{68}\)Ga-Labeled Nanoparticles
### Iron Oxide Nanoparticles (IONPs)
To radiolabel their SPIONs, they incubated GaCl\({}_{3}\) with SPIONs in 1M acetate buffer pH 5.5 for different times to assess the best fitting one. They obtained 95% radiolabeling efficiency within 10 min and managed to achieve 97.3% after 15 min of incubation. \({}^{68}\)Ga-labeled SPIONs proved to be stable in human serum at 37 \({}^{\circ}\)C for 4 h. These SPIONs served as a dual probe for PET/MR imaging of Sentinel Lymph Nodes (SLN), the first node receiving lymphatic drainage from the primary tumor site, in rat models (Figure 5). [PERSON] et al. [69] utilized [PERSON] and coworkers' [70]\({}^{68}\)Ga-SPIONs as a contrast agent for magnetomotive ultrasound (MMUS); a novel ultrasound-based method for intra-surgical guidance to localize metastases during cancer surgery. In their study, \({}^{68}\)Ga-SPIONs served as a dual-imaging probe for pre-operative PET/MRI imaging followed by intra-operative MMUS imaging in a SLN rat model. [PERSON] et al. [99] used amphiphile-encapsulated iron oxide nanoparticles, radiolabeled with \({}^{68}\)Ga using NOTA chelate ligand, to monitor lymph node uptake via PET and T\({}_{2}\)-weighted MR imaging. High radiochemical yield was obtained (<95%) and stability in human serum was tested in human serum by gel filtration at 37 \({}^{\circ}\)C, suggesting nanoparticles are stable in human serum under physiological conditions. Over the last few decades, numerous discoveries have enlightened molecular bases of cancer. This in conjunction with the lack of implementations to study molecular events in depth has motivated the quest for novel approaches in cancer detection. Several groups have focused on the development of radiolabeled nanoprobes for the detection of this disease. Passive accumulation of nanoradiotracers in tumors, due to enhanced permeability and retention (EPR) effect, has been widely used as a delivery strategy to locate carcinogenic tissue [6; 107; 108]. EPR effect is the increased permeation of blood vessels to tumor interstitial space, surrounding tumor environments. They allow delivery and retention of drugs and imaging agents with moderated specificity [109; 110]. Even though passive accumulation of NPs in the tumor site has proven to be a valuable method for imaging angiogenesis, active targeting of cancerous cells by means of tumor targeting moieties substantially increases probe specificity providing better quality images. [PERSON] et al. (2016) conjugated PEG-coated \({}^{68}\)Ga-NOTA-IONPs with oleanolic acid (OA), a novel tumor targeting molecule, to specifically target HT-29 cancer cells in a murine model ([PERSON] et al., 2016). Functional amines in PEG coating enabled tumor targeting moiety (oleanolic acid) and chelating agent for \({}^{68}\)Ga (NOTA) incorporation. With this approach, they could visualize the xenograft tumor in vivo using PET/MRI imaging. Furthermore, [PERSON] et al. (2017) developed prostate-specific membrane antigen (PSMA) targeting IONPs for in vivo PET and MR imaging of mouse prostate cancer xenograft models, revealing specific accumulation in tumor site. For this purpose, IONPs were encapsulated with amphiphiles containing PEG, DOTA and glutamate-urea-lysine (GUL), the PSMA targeting ligand; and subsequently radiolabeled with \({}^{68}\)Ga obtaining 99% efficiency. Radiochemical purity of the final radiolabeled nanoprobe was higher than 99%. [PERSON] et al. (2016) obtained via microwave-assisted synthesis a core-doped hybrid nanoradiotracer, \({}^{68}\)Ga core-doped dextran-coated IONPs, that was posteriorly conjugated to RGD peptide via 1,4-(butanediol) diglycidyl ether homobifunctional crosslinker, to target angiogenesis in a subcutaneous melanoma murine model. To core dope the nanoparticles, \({}^{68}\)GaCl\({}_{3}\) eluate was added to initial precursors and mixture introduced into the microwave for 10 min at 100 \({}^{\circ}\)C. Radiolabeling yield obtained was 93.4%. In vivo PET and T\({}_{1}\)-weighted MRI experiments confirmed specific tumor accumulation of the \({}^{68}\)Ga-C-IONP-RGD probe.