Gold nanoparticle detection and quantification in therapeutic MV beams via pair production.

PURPOSE: We propose a new detection method of gold nanoparticles (AuNP) in therapeutic megavoltage (MV) x-ray beams by means of coincidence counting of annihilation photons following pair production in gold. METHODS: The proposed MV x-ray induced positron emission (MVIPE) imaging technique is studied by radiation transport computations using MCNP6 (3D) and CEPXS/ONEDANT (1D) codes for two water phantoms: a 35 cm slab and a similarly sized cylinder, both having a 5 cm AuNP filled region in the center. MVIPE is compared to the standard x-ray fluorescence computed tomography (XFCT). MVIPE adopts MV x-ray sources (Co-60, 2 MV, 6 MV, 6 MV with closed MLC and 15 MV) and relies on the detection of 511 keV photon-pairs. XFCT uses kilovoltage sources (100 kVp, 120 kVp and 150 kVp) and imaging is characterized by analysis of k α1,2 Au characteristic lines. Three levels of AuNP concentration were studied: 0.1%, 1% and 10% by weight. RESULTS: Annihilation photons in the MVIPE technique originate both in the AuNP and in water along the x-ray beam path with significantly larger production in the AuNP-loaded region. MVIPE signal from AuNP is linearly increasing with AuNP concentration up to 10%wt, while XFCT signal reaches saturation due to self-absorption within AuNP. The production of annihilation photons is proportional to the MV source energy. MVIPE technique using a 15 MV pencil beam and 10 wt% AuNP detects about 4.5 × 103 511 keV-photons cm-2 at 90° w/r to the incident beam per 109 source photons cm-2; 500 of these come from AuNP. In contrast, the XFCT technique using 150 kVp detects only about 100 k α1-photons cm-2 per 109 source photons cm-2. CONCLUSIONS: In MVIPE, the number of annihilation photons produced for different MV-beam energies and AuNP concentrations is significantly greater than the k α1 photons generated in XFCT. Coincidence counting in MVIPE allows to avoid collimation, which is a major limiting factor in XFCT. MVIPE challenges include the filtering of Compton scatter and annihilation photons originating in water.

A Monte Carlo study of I-125 prostate brachytherapy with gold nanoparticles: dose enhancement with simultaneous rectal dose sparing via radiation shielding.

We investigate via Monte Carlo simulations a new 125I brachytherapy treatment technique for high-risk prostate cancer patients via injection of Au nanoparticle (AuNP) directly into the prostate. The purpose of using the nanoparticles is to increase the therapeutic index via two synergistic effects: enhanced energy deposition within the prostate and simultaneous shielding of organs at risk from radiation escaping from the prostate. Both uniform and non-uniform concentrations of AuNP are studied. The latter are modeled considering the possibility of AuNP diffusion after the injection using brachy needles. We study two extreme cases of coaxial AuNP concentrations: centered on brachy needles and centered half-way between them. Assuming uniform distribution of 30 mg g-1 of AuNP within the prostate, we obtain a dose enhancement larger than a factor of 2 to the prostate. Non-uniform concentration of AuNP ranging from 10 mg g-1 and 66 mg g-1 were studied. The higher the concentration in a given region of the prostate the greater is the enhancement therein. We obtain the highest dose enhancement when the brachytherapy needles are coincident with AuNP injection needles but, at the same time, the regions in the tail are colder (average dose ratio of 0.7). The best enhancement uniformity is obtained with the seeds in the tail of the AuNP distribution. In both uniform and non-uniform cases the urethra and rectum receive less than 1/3 dose compared to an analog treatment without AuNP. Remarkably, employing AuNP not only significantly increases dose to the target but also decreases dose to the neighboring rectum and even urethra, which is embedded within the prostate. These are mutually interdependent effects as more enhancement leads to more shielding and vice-versa. Caution must be paid since cold spot or hot spots may be created if the AuNP concentration versus seed position is not properly distributed respect to the seed locations.

Comment on: Polarity effects and apparent ion recombination in microionization chambers Med. Phys. 43(5), 2141-2152 (2016).

In a recent paper of Miller et al. (Med. Phys. 43(5), 2141-2152 (2016), the voltage dependence polarity effect of microionization chambers was studied. It was identified that polarity effect arises from the difference in electric potential between the collecting electrode and the guard electrode, which in turn deforms the electric field and affects the charge collection. Nevertheless, the cause of such potential difference has not been identified. In this letter, we explain that the electric potential perturbation arises from the work function difference of the disparate materials electrodes (collecting vs guard electrodes in the particular case).

The radiosensitizing effect of the aurora kinase inhibitors, ENMD-2076, on canine mast cell tumours in vitro.

ENMD-2076 is an aurora kinase inhibitor that also has multi-target tyrosine kinase inhibitor properties. In this study, the mRNA and the protein expression of aurora-A and aurora-B were evaluated in three canine mast cell tumour cell lines. Dose-dependent cytotoxicity was seen in the cells treated, and it affected the cell cycle with cells in the G2/M phase being selectively killed. The cells were also evaluated for radiosensitivity with/without ENMD-2076, and radiosensitization was seen after 3 Gy and 6 Gy exposures with ENMD-2076 for 48 h. Protein expression of caspase-3 was gradually increased, and the expression intensity was highest at 24 h post irradiation in cells without ENMD-2076 treatment, which indicates that radiation exposure with ENMD-2076-induced cell death faster than radiation treatment alone. Our study results suggest the potential usefulness of treating canine mast cell tumours with aurora kinase inhibitors alone or in conjunction with radiation therapy.

Kilovoltage radiosurgery with gold nanoparticles for neovascular age-related macular degeneration (AMD): a Monte Carlo evaluation.

This work uses Monte Carlo radiation transport simulation to assess the potential benefits of gold nanoparticles (AuNP) in the treatment of neovascular age-related macular degeneration with stereotactic radiosurgery. Clinically, a 100 kVp x-ray beam of 4 mm diameter is aimed at the macula to deliver an ablative dose in a single fraction. In the transport model, AuNP accumulated at the bottom of the macula are targeted with a source representative of the clinical beam in order to provide enhanced dose to the diseased macular endothelial cells. It is observed that, because of the AuNP, the dose to the endothelial cells can be significantly enhanced, allowing for greater sparing of optic nerve, retina and other neighboring healthy tissue. For 20 nm diameter AuNP concentration of 32 mg g(-1), which has been shown to be achievable in vivo, a dose enhancement ratio (DER) of 1.97 was found to be possible, which could potentially be increased through appropriate optimization of beam quality and/or AuNP targeting. A significant enhancement in dose is seen in the vicinity of the AuNP layer within 30 µm, peaked at the AuNP-tissue interface. Different angular tilting of the 4 mm beam results in a similar enhancement. The DER inside and in the penumbra of the 4 mm irradiation-field are almost the same while the actual delivered dose is more than one order of magnitude lower outside the field leading to normal tissue sparing. The prescribed dose to macular endothelial cells can be delivered using almost half of the radiation allowing reduction of dose to the neighboring organs such as retina/optic nerve by 49% when compared to a treatment without AuNP.

Targeted radiotherapy enhancement during electronic brachytherapy of accelerated partial breast irradiation (APBI) using controlled release of gold nanoparticles.

Several studies have demonstrated low rates of local recurrence with brachytherapy-based accelerated partial breast irradiation (APBI). However, long-term outcomes on toxicity (e.g. telangiectasia) and cosmesis remain a major concern. The purpose of this study is to investigate the dosimetric feasibility of using targeted non-toxic radiosensitizing gold nanoparticles (GNPs) for localized dose enhancement to the planning target volume (PTV) during electronic brachytherapy APBI while reducing normal tissue toxicity. We propose to incorporate GNPs into a micrometer-thick polymer film on the surface of routinely used lumpectomy balloon applicators and provide subsequent treatment using a 50 kVp Xoft device. An experimentally determined diffusion coefficient was used to determine space-time customizable distribution of GNPs for feasible in-vivo concentrations of 7 mg/g and 43 mg/g. An analytical approach from previously published work was employed to estimate the dose enhancement due to GNPs as a function of distance up to 1 cm from the lumpectomy cavity surface. Clinically significant dose enhancement values of at least 1.2, due to 2 nm GNPs, were found at 1 cm away from the lumpectomy cavity wall when using electronic brachytherapy APBI. Higher customizable dose enhancement was also achieved at other distances as a function of nanoparticle size. Our preliminary results suggest that significant dose enhancement can be achieved to residual tumor cells targeted with GNPs during APBI with electronic brachytherapy.

A Software App for Radiotherapy with In-situ Dose-painting using high Z nanoparticles.

The purpose of this work is to develop an user friendly and free-to-download application software that can be employed for modeling Radiotherapy with In-situ Dose-painting (RAID) using high-Z nanoparticles (HZNPs). The RAID APP is software program written in Matlab (Mathworks, Natick, MA, USA) based on deterministic code developed to simulate the space-time intra-tumor HZNPs biodistribution within the tumor, and the corresponding dose enhancement in response to low dose rate (LDR) brachytherapy of I-125, Pd-102, Cs-131 and kilovoltage x-rays such as 50 keV and 100 keV. Through the GUI of RAID APP, the user will be directed to different features to compute various parameters related to the dose enhancement and the biodistribution of NPs within high risk tumor sub-volumes. The software was developed as tool for research purposes with potential for subsequent development to guide dose-painting treatment planning using radiosensitizers such as gold (Au) and platinum (Pt).

Low-Z linac targets for low-MV gold nanoparticle radiation therapy.

PURPOSE: To investigate the potential of low-Z/low-MV (low-Z) linac targets for gold nanoparticle radiotherapy (GNPT) and to determine the microscopic dose enhancement ratio (DER) due to GNP for the alternative beamlines. In addition, to evaluate the degradation of dose enhancement arising from the increased attenuation of x rays and larger skin dose in water for the low-MV beams compared to the standard linac. METHODS: Monte Carlo simulations were used to compute dose and DER for various flattening-filter-free beams (2.5, 4, 6.5 MV). Target materials were beryllium, diamond, and tungsten-copper high-Z target. Target thicknesses were selected based on 20%, 60%, 70%, and 80% of the continuous slowing down approximation electron ranges for a given target material and energy. Evaluation of the microscopic DER was carried out for 100 nm GNP including the degradation factors due to beam attenuation. RESULTS: The greatest increase in DER compared to the standard 6.5 MV linac was for a 2.5 MV Be-target (factor of ∼ 2). Skin dose ranged from ∼ 10% (Be, 6.5 MV-80%) to ∼ 85% (Be, 2.5 MV-20%) depending on the target case. Attenuation of 2.5 MV beams at 22 cm was higher by ∼ 75% compared with the standard beam. Taking into account the attenuation at 22 cm depth, the effective dose enhancement was up to ∼ 60% above the DER of the high-Z target. For these cases the effective DER ranged between ∼ 1.6 and 6 compared with the standard linac. CONCLUSIONS: Low-Z (2.5 MV) GNPT is possible even after accounting for greater beam attenuation for deep-seated tumors (22 cm) and the increased skin dose. Further, it can lead to significant sparing of normal tissue while simultaneously escalating the dose in the tumor cells.

Beam quality and dose perturbation of 6 MV flattening-filter-free linac.

The aim of this study is twofold: (a) determination of the spectral differences for flattening-filter-free (FFF) versus standard (STD) linac under various clinical conditions, (b) based on an extensive list of clinically important beam configurations, identification of clinical scenarios that lead to higher macroscopic dose perturbations due to the presence of high-Z material. The focus is on dose enhancement due to contrast agents including high-Z elements such as gold or gadolinium. EGSnrc was used to simulate clinical beams under various irradiation conditions: open/IMRT/spit-IMRT fields, in/out-off-field areas, different depths and field sizes. Spectra were calculated and analyzed for about 80 beams and for a total of 480 regions. Quantitative differential effects in beam quality were characterized using energy-dependent and cumulative dose perturbation metrics. Analysis of the spectral database showed that even though the general trends for both linacs (FFF/STD) were the same, there were crucial differences. In general, the relative changes between different conditions were smaller for FFF spectra. This was because of the higher component of low-energy photons of the FFF linac, which already lead to higher dose enhancement than for the STD linac (photon energies were more "uniformly" distributed for FFF spectra and henceforth their perturbation resulted in lesser relative changes). For out-of-field FFF spectra and split-IMRT fields the strongest enhancement were observed (∼25 and ∼5 respectively). Different spectral scenarios lead to different dose enhancements, however, they scale with the higher effective-Z of the materials and were directly related to the lower range of the spectra (<200 keV).

Radiosensitivity of canine osteosarcoma cells transfected with wild-type p53 in vitro.

The p53 gene is one of the important tumour suppressor genes that are involved with the cell survival signal pathway. One of the major functions of the p53 protein is to organize cell cycle regulation and induction of apoptosis for cellular genetic stability. It has been documented that more than 50% of all human cancers include a p53 mutation. We evaluated the difference in radiosensitivity between upregulating the expression of canine wild-type p53 (cp53) in cultured osteosarcoma (D17) cells and naive D17 cells in vitro. We found that upregulating transfected cp53 D17 cells increased their radiation sensitivity in vitro, and there was a significant decrease (P < 0.009) in survival between cp53-transfected D17 cells and naive D17 cells. In this experiment, a p53 enhancement ratio (p53ER) reached approximately 3.0 at high doses. The transfected cp53 D17 cells were significantly more radiosensitive at all doses evaluated than naive D17 cells, except at 1 Gy where too few data points were available. The p53ER increased rapidly at doses less than 4 Gy, achieving a maximum of about 3.0 for doses of 4 Gy and above. This study shows the enhanced radiosensitivity of the transfected p53 at clinically relevant doses.

Deterministic photon transport calculations in general geometry for external beam radiation therapy.

A deterministic method is described for performing three-dimensional (3D) photon transport calculations of a LINAC head and phantom/patient geometry to obtain dose distributions for therapy planning. The space, energy, and directional-dependent photon flux density is obtained by numerically solving the Boltzmann equation in general 3D geometry using the method of characteristics. The deterministic transport calculations use similar ray tracing routines as found in Monte Carlo (MC) codes. A special treatment is developed to better represent the impact of scattering from accelerator head components. Equations are presented for computing the water kerma distribution due to the uncollided and collided photon flux density field in the patient region. Kerma results obtained from the deterministic computation are compared to Monte Carlo values for a variety of source spectra and field sizes. The agreement for kerma values in the beam is usually within the MC uncertainties. It is concluded that the deterministic method is a rigorous, first-principles approach that could provide a superior alternative to Monte Carlo calculations for some types of problems. However additional development is needed to provide capability for 3D electron transport calculations.

Spatial distribution of indoor aerosol deposition under accidental release conditions.

Indoor aerosol dispersion and particle deposition was investigated using a series of puff releases of nonspecific activatable tracers simulating an accidental source. Initial particle size distribution included the respirable range, with most of the particles between 0.5 to 5.0 microm. Tracers were released in a nuclear laboratory/work environment and were collected via passive collector foils to obtain the spatial distribution of deposition. The observed distribution characteristics did not always correspond to the measured air flow patterns, and they showed a non-negligible dependence on aerosol dynamics such as thermophoretic effects. The collected data represent integrated deposition flux, which can serve for validation of aerosol dynamics models that aim to predict the deposition fluence of particles and may also be used for planning surface contamination surveys following accidental releases.

Deterministic calculations of photon spectra for clinical accelerator targets.

A method is proposed to compute photon energy spectra produced in clinical electron accelerator targets, based on the deterministic solution of the Boltzmann equation for coupled electron-photon transport in one-dimensional (1-D) slab geometry. It is shown that the deterministic method gives similar results as Monte Carlo calculations over the angular range of interest for therapy applications. Relative energy spectra computed by deterministic and 3-D Monte Carlo methods, respectively, are compared for several realistic target materials and different electron beams, and are found to give similar photon energy distributions and mean energies. The deterministic calculations typically require 1-2 mins of execution time on a Sun Workstation, compared to 2-36 h for the Monte Carlo runs.

A historically controlled trial of tyrosine for cocaine dependence.

Cocaine dependence continues to be a major public health problem and efforts to develop pharmacotherapies have been disappointing. Chronic cocaine use is believed to cause catecholamine depletion and similarities exist between cocaine withdrawal and major depression. Tyrosine is the dietary precursor to catecholamines and has yielded positive results in small trials of its antidepressant efficacy. Tyrosine 2 g every 8 hours was administered on an open-label basis to 49 cocaine-dependent individuals, as an adjunct to intensive out-patient drug abuse counseling. Retention in treatment at 90 days was compared to data from a control group of 80 subjects who had received 10 mg of imipramine per day in an earlier trial. Median retention was 17 days in both groups. No side effects were reported by the subjects receiving tyrosine. These results do not support the utility of tyrosine in the treatment of cocaine dependence.