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Iron oxide nanoparticles are the most extensively explored magnetic materials in nanomedicine, with applications as drug delivery agents, probes for magnetic particle imaging, and contrast agents for magnetic resonance imaging (MRI). Furthermore, radiolabelling of these nanomaterials has emerged in the last years as a very promising tool for molecular imaging applications; the possibility of obtaining Gallium-66/68 after proton irradiation of tissues offers the possibility of testing these nanoparticles as protoactivable probes with the aim to use PET/CT imaging for dose verification after proton therapy. Here, we want to present the initial work about iron oxide nanoparticle doped with zinc and coated with citrate (IONP@Zn-cit). MTT assay was applied to assess the nanoparticles-induced cytotoxicity in several cell lines: A549 (type II pulmonary epithelial cell from a human lung adenocarcinoma), U251 (cell line from a malignant glioblastoma tumour) and V79 (fibroblast from a Hamster Chinese lung). Incubation of different amounts of nanoparticles for 24 hours in cell culture conditions showed differences in the response among the three cell lines (Figure a). IONP@Zn-cit induced cell cytotoxicity in a concentration dependent manner; EC50 concentrations (reducing survival by 50%) ranged from 0.05-0.08 mg/mL of Fe concentration and 0.07-0.12 mg/mL of Zn, being U251 and A549 the most and the least sensitive cell lines respectively. Parallelly, we tested de visu the stability of the IONP@Zn-cit in DMEM cell culture medium alone or supplemented with 10% of Fetal Bovine Serum (FBS), resulting on the increasing of colloidal stability in culture medium with FBS. Finally, nanoparticle biodistribution was assessed inoculating Gallium-67 IONP@Zn-cit core doped nanoparticles synthesized by a microwave-driven protocol in a xenograft U251 murine model at 6 hours, 1, 3 and 7 days after intravenous injection. The results showed major accumulation of 67Ga-IONP@Zn-cit at 1-day post inoculation in liver (33.71 %ID/g) and spleen (32.23 %ID/g), common elimination pathway for these type of nanoparticles, followed by bone (4.41 %ID/g) and with a tumour uptake value of 0.95 %ID/g (Figure b). These results were consistent with the published before with IONP-cit nanoparticles pointing out the role of the mononuclear phagocytic system on nanoparticle biodistribution. Non-compartmental pharmacokinetic analysis of plasma data was performed using PK Solver 2.0 software. The terminal phase half-life and the mean residence time were 3.9 and 2.8 days, respectively. The blood clearance was very low (0.43 mL/d/kg). In conclusion, tumour uptake of nanoparticles presented here would be useful for validation of dose deposition with protons and, moreover, it could be improve by active-targeting.
