Determining dose enhancement factors of high-Z nanoparticles from simulations where lateral secondary particle disequilibrium exists.

Nanoparticles (NPs) containing high atomic number (high-Z) materials have been shown to enhance the radiobiological effectiveness of ionizing radiation. This effect is often attributed to an enhancement of the absorbed dose in the vicinity of the NPs, based on Monte Carlo simulations that show a significant local enhancement of the energy deposition on the microscopic scale. The results of such simulations may be significantly biased and lead to a severe overestimation of the dose enhancement if the condition of secondary particle equilibrium is not met in the simulation setup. This current work shows an approach to estimate a 'realistic' dose enhancement from the results of such biased simulations which is based on published photon interaction data and provides a way for correcting biased results.

Biocompatibility assessment of up-and down-converting nanoparticles: implications of interferences with in vitro assays.

The safety assessment of nanoparticles (NPs) is crucial during their design and development for biomedicine. One of the prerequisite steps during this evaluation is in vitro testing that employs cell-based assays not always validated and well-adapted for NPs. Interferences with in vitro assays may arise due to the nano-related optical, oxidative, fluorescent, surface and catalytic properties of NPs. Thus, proper validation of each assay system has to be performed for each NP type. This study aimed to evaluate the applicability of the most common in vitro cytotoxicity assays for the safety assessment of up- and down-converting lanthanide-doped NPs. Conventional cell viability tests and fluorescence-based assays for oxidative stress response were selected to determine the biological effects of up- and down-converting NPs to human brain cells. Comparison with known silver and iron oxide NPs was made for verification purposes. Both the plate reader and flow cytometric measurements were examined. The obtained results indicated that both types of Ln-doped NPs interfered to a much lesser extent than metallic NPs. In addition, the great potential of both up- and down-converting NPs for biomedicine was manifested due to their biocompatibility and low toxicity.

Nanoscale dose deposition in cell structures under X-ray irradiation treatment assisted with nanoparticles: An analytical approach to the relative biological effectiveness.

In this study, an analytical model for the assessment of the modification of cell culture survival under ionizing radiation assisted with nanoparticles (NPs) is presented. The model starts from the radial dose deposition around a single NP, which is used to describe the dose deposition in a cell structure with embedded NPs and, in turn, to evaluate the number of lesions formed by ionizing radiation. The model is applied to the calculation of relative biological effectiveness values for cells exposed to 0.5mg/g of uniformly dispersed NPs with a radius of 10nm made of Fe, I, Gd, Hf, Pt and Au and irradiated with X-rays of energies 20keV higher than the element K-shell binding energy.

Impact of fluorescence emission from gold atoms on surrounding biological tissue-implications for nanoparticle radio-enhancement.

The addition of gold nanoparticles within target tissue (i.e. a tumour) to enhance the delivered radiation dose is a well studied radiotherapy treatment strategy, despite not yet having been translated into standard clinical practice. While several studies have used Monte Carlo simulations to investigate radiation dose enhancement by Auger electrons emitted from irradiated gold nanoparticles, none have yet considered the effects due to escaping fluorescence photons. Geant4 was used to simulate a water phantom containing 10 mg ml-1 uniformly dispersed gold (1% by mass) at 5 cm depth. Incident monoenergetic photons with energies either side of the gold K-edge at 73 keV and 139.5 keV were chosen to give the same attenuation contrast against water, where water is used as a surrogate for biological tissue. For 73 keV incident photons, adding 1% gold into the water phantom enhances the energy deposited in the phantom by a factor of ≈1.9 while 139.5 keV incident photons give a lower enhancement ratio of ≈1.5. This difference in enhancement ratio, despite the equivalent attenuation ratios, can be attributed to energy carried from the target into the surrounding volume by fluorescence photons for the higher incident photon energy. The energy de-localisation is maximal just above the K-edge with 36% of the initial energy deposit in the phantom lost to escaping fluorescence photons. Conversely we find that the absorption of more photons by gold in the phantom reduces the number of scattered photons and hence energy deposited in the surrounding volume by up to 6% for incident photons below the K-edge. For incident photons above the K-edge this is somewhat offset by fluorescence. Our results give new insight into the previously unstudied centimetre scale energy deposition outside a target, which will be valuable for the future development of treatment plans using gold nanoparticles. From these results, we can conclude that gold nanoparticles delivered to a target tumour are capable of increasing dose to the tumour whilst simultaneously decreasing scatter dose to surrounding healthy tissue.

Toxicity assessment of anatase and rutile titanium dioxide nanoparticles: The role of degradation in different pH conditions and light exposure.

Titanium dioxide nanoparticles (TiO2NPs), in the two crystalline forms, rutile and anatase, have been widely used in many industrial fields, especially in cosmetics. Therefore, a lot of details about their safety issues have been discussed by the scientific community. Many studies have led to a general agreement about TiO2NPs toxicity, in particular for anatase form, but no mechanism details have been proved yet. In this study, data confirm the different toxic potential of rutile and anatase TiO2NPs in two cell lines up to 5nM nanoparticles concentration. Moreover, we evaluated the role of titanium ions released by TiO2NPs in different conditions, at pH=4.5 (the typical lysosomal compartment pH) and at pH=5.5 (the skin physiological pH) in conditions of darkness and light, to mimic the dermal exposure of cosmetics. Anatase nanoparticles were proner to degradation both in the acidic conditions and at skin pH. Our study demonstrates that pH and sunlight are dominant factors to induce oxidative stress, TiO2NPs degradation and toxicity effects.

Study of the effect of ceramic Ta2O5 nanoparticle distribution on cellular dose enhancement in a kilovoltage photon field.

The application of nanoparticles (NPs) in radiotherapy is an increasingly attractive technique to improve clinical outcomes. The internalisation of NPs within the tumour cells enables an increased radiation dose to critical cellular structures. The purpose of this study is to investigate, by means of Geant4 simulations, the dose enhancement within a cell population irradiated with a 150kVp photon field in the presence of a varying concentration of tantalum pentoxide (Ta2O5) NP aggregates, experimentally observed to form shells within tumour cells. This scenario is compared to the more traditionally simulated homogeneous solution of NP material in water with the same weight fraction of Ta2O5, as well as to a cell population without NPs present. The production of secondary electrons is enhanced by increased photoelectric effect interactions within the high-Z material and this is examined in terms of their kinetic energy spectra and linear energy transfer (LET) with various NP distributions compared to water. Our results indicate that the shell formation scenario limits the dose enhancement at 150kVp. The underlying mechanism for this limit is discussed.

Size-Tuning Ionization To Optimize Gold Nanoparticles for Simultaneous Enhanced CT Imaging and Radiotherapy.

Computed tomography (CT) contrast and radiosensitization usually increase with particle sizes of gold nanoparticles (AuNPs), but there is a huge challenge to improve both by adjusting sizes under the requirements of in vivo application. Here, we report that AuNPs have great size-dependent enhancements on CT imaging as well as radiotherapy (RT) in the size range of 3-50 nm. It is demonstrated that AuNPs with a size of ∼13 nm could simultaneously possess superior CT contrast ability and significant radioactive disruption. The Monte Carlo method is further used to evaluate this phenomenon and indicates that the inhomogeneity of gold atom distributions caused by sizes may influence secondary ionization in whole X-ray interactions. In vivo studies further indicate that this optimally sized AuNP improves real-time CT imaging and radiotherapeutic inhibition of tumors in living mice by effective accumulation at tumors with prolonged in vivo circulation times compared to clinically used small-molecule agents. These results suggest that ∼13 nm AuNPs may serve as multifunctional adjuvants for clinical X-ray theranostic application.

Experimental assessment of gold nanoparticle-mediated dose enhancement in radiation therapy beams using electron spin resonance dosimetry.

In this work, we aim to experimentally assess increments of dose due to nanoparticle-radiation interactions via electron spin resonance (ESR) dosimetry performed with a biological-equivalent sensitive material.We employed 2-Methyl-Alanine (2MA) in powder form to compose the radiation sensitive medium embedding gold nanoparticles (AuNPs) 5 nm in diameter. Dosimeters manufactured with 0.1% w/w of AuNPs or no nanoparticles were irradiated with clinically utilized 250 kVp orthovoltage or 6 MV linac x-rays in dosimetric conditions. Amplitude peak-to-peak (App) at the central ESR spectral line was used for dosimetry. Dose-response curves were obtained for samples with or without nanoparticles and each energy beam. Dose increments due to nanoparticles were analyzed in terms of absolute dose enhancements (DEs), calculated as App ratios for each dose/beam condition, or relative dose enhancement factors (DEFs) calculated as the slopes of the dose-response curves.Dose enhancements were observed to present an amplified behavior for small doses (between 0.1-0.5 Gy), with this effect being more prominent with the kV beam. For doses between 0.5-5 Gy, dose-independent trends were observed for both beams, stable around (2.1 ± 0.7) and (1.3 ± 0.4) for kV and MV beams, respectively. We found DEFs of (1.62 ± 0.04) or (1.27 ± 0.03) for the same beams. Additionally, we measured no interference between AuNPs and the ESR apparatus, including the excitation microwaves, the magnetic fields and the paramagnetic radicals.2MA was demonstrated to be a feasible paramagnetic radiation-sensitive material for dosimetry in the presence of AuNPs, and ESR dosimetry a powerful experimental method for further verifications of increments in nanoparticle-mediated doses of biological interest. Ultimately, gold nanoparticles can cause significant and detectable dose enhancements in biological-like samples irradiated at both kilo or megavoltage beams.

Production of medical radioisotopes with linear accelerators.

In this study, we discuss producing radioisotopes using linear electron accelerators and address production and separation issues of photoneutron (γ,n) and photoproton (γ,p) reactions. While (γ,n) reactions typically result in greater yields, separating product nuclides from the target is challenging since the chemical properties of both are the same. Yields of (γ,p) reactions are typically lower than (γ,n) ones, however they have the advantage that target and product nuclides belong to different chemical species so their separation is often not such an intricate problem. In this paper we consider two examples, (100)Mo(γ,n)(99)Mo and (68)Zn(γ,p)(67)Cu, of photonuclear reactions. Monte-Carlo simulations of the yields are benchmarked with experimental data obtained at the Idaho Accelerator Center using a 44MeV linear electron accelerator. We propose using a kinematic recoil method for photoneutron production. This technique requires (100)Mo target material to be in the form of nanoparticles coated with a catcher material. During irradiation, (99)Mo atoms recoil and get trapped in the coating layer. After irradiation, the coating is dissolved and (99)Mo is collected. At the same time, (100)Mo nanoparticles can be reused. For the photoproduction method, (67)Cu can be separated from the target nuclides, (68)Zn, using standard exchange chromatography methods. Monte-Carlo simulations were performed and the (99)Mo activity was predicted to be about 7MBq/(g(⁎)kW(⁎)h) while (67)Cu activity was predicted to be about 1MBq/(g(⁎)kW(⁎)h). Experimental data confirm the predicted activity for both cases which proves that photonuclear reactions can be used to produce radioisotopes. Lists of medical isotopes which might be obtained using photonuclear reactions have been compiled and are included as well.

Microdosimetry of X-ray-irradiated gold nanoparticles.

The use of contrast agents, particularly those made of high atomic number elements like gold nanoparticles, to enhance the X-ray absorption properties of tissue has recently gained attention in the context of radiotherapy treatments. Because these contrast agents alter the secondary electron field in the irradiated medium by adding an Auger electron component, it is necessary to determine the change in the microdosimetric spectra brought about by the incorporation of such agents. Using Monte Carlo simulation, it is shown that the linear energy transfer and the beam quality factor in the vicinity of a gold nanoparticle irradiated with kilovoltage X-ray beams increase substantially when compared with irradiation without the gold nanoparticles present.