ABSTRACT
Background: Gold nanoparticles (AuNPs) are considered as promising agents to increase the radiosensitivity of tumor cells. However, the biological mechanisms of radiation enhancement effects of AuNPs are still not well understood. We present a multi-scale Monte Carlo simulation framework within TOPAS-nBio to investigate the increase of DNA damage due to the presence of AuNPs in mouse tumor models. Methods: A tumor was placed inside a voxel mouse model and irradiated with either 100 kVp or 200 kVp x-ray beams. Phase spaces were employed to transfer particles from the macroscopic (voxel) scale to the microscopic scale, which consists of a cell geometry including a detailed mouse DNA model. Radiosensitizing effects were calculated in the presence and absence of hybrid nanoparticles with a Fe2O3 core surrounded by a gold layer (AuFeNPs). To simulate DNA damage even for very small energy tracks, Geant4-DNA physics and chemistry models were used on microscopic scale. Results: An AuFeNP induced enhancement of both dose and DNA strand breaks has been established for different scenarios. Produced chemical radicals including hydroxyl molecules, which were assumed to be responsible for DNA damage through chemical reactions, were found to be significantly increased. We further observed a dependency of the results on the location of the cells within the tumor for 200 kVp x-ray beams. Conclusions: Our multi-scale approach allows to study irradiation induced physical and chemical effects on cells. We showed a potential increase in cell radiosensitization caused by relatively small concentrations of AuFeNPs. Our new methodology allows the individual adjustment of parameters in each simulation step and therefore can be used for other studies investigating the radiosensitizing effects of AuFeNPs or AuNPs in living cells.
ABSTRACT
BACKGROUND: Superparamagnetic iron oxide nanoparticles (SPIONs) have displayed multifunctional applications in cancer theranostics following systemic delivery. In an effort to increase the therapeutic potential of local therapies (including focal hyperthermia), nanoparticles can also be administered intratumorally. Therefore, the development of a reliable pharmacokinetic model for the prediction of nanoparticle distribution for both clinically relevant routes of delivery is of high importance. MATERIALS AND METHODS: The biodistribution of SPIONs (of two different sizes - 130 nm and 60 nm) radiolabeled with zirconium-89 or technetium-99m following intratumoral or intravenous injection was investigated in C57/Bl6 mice bearing subcutaneous GL261 glioblastomas. Based on PET/CT biodistribution data, a novel pharmacokinetic model was established for a better understanding of the pharmacokinetics of the SPIONs after both administration routes. RESULTS: The PET image analysis of the nanoparticles (confirmed by histology) demonstrated the presence of radiolabeled nanoparticles within the glioma site (with low amounts in the liver and spleen) at all investigated time points following intratumoral injection. The mathematical model confirmed the dynamic nanoparticle redistribution in the organism over a period of 72 h with an equilibrium reached after 100 h. Intravenous injection of nanoparticles demonstrated a different distribution pattern with a rapid particle retention in all organs (particularly in liver and spleen) and a subsequent slow release rate. CONCLUSION: The mathematical model demonstrated good agreement with experimental data derived from tumor mouse models suggesting the value of this tool to predict the real-time pharmacokinetic features of SPIONs in vivo. In the future, it is planned to adapt our model to other nanoparticle formulations to more precisely describe their biodistribution in in vivo model systems.
