Monte Carlo Simulations Corroborate PET-Measured Discrepancies in Activity Assessments of Commercial 90Y Vials.

In a recent multicenter study, discrepancies between PET/CT-measured activity and vendor-calibrated activity for 90Y glass and resin microspheres were found. In the present work, the origin of these discrepancies was investigated by Monte Carlo (MC) simulations. Methods: Three vial configurations, containing 90Y-chloride, 90Y-labeled glass microspheres, and 90Y-labeled resin microspheres, were modeled with GAMOS, and the electric signal generated in an activity meter was simulated. Energy deposition was scored in the activity meter-active regions and converted into electric current per unit activity. Internal bremsstrahlung (IB) photons, always accompanying ß-decay, were simulated in addition to 90Y decays. The electric current per source activity obtained for 90Y glass and resin microspheres, Iglass and Iresin, was compared in terms of relative percentage difference with that of 90Y-chloride ([Formula: see text] and [Formula: see text]) and each other (δ). The findings of this work were compared with the ones obtained through PET measurements in the multicenter study. Results: With the inclusion of IB photons as primary particles in MC simulations, the [Formula: see text] and [Formula: see text] results were 24.6% ± 3.9% and -15.0% ± 2.2%, respectively, whereas δ was 46.5% ± 1.9%, in very good agreement with the values reported in the multicenter study. Conclusion: The MC simulations performed in this study indicate that the discrepancies recently found between PET/CT-measured activity and vendor-calibrated activity for 90Y glass and resin microspheres can be attributed to differences in the geometry of the respective commercial vials and to the metrologic approach adopted for activity meter calibration with a 90Y-chloride liquid source. Furthermore, IB photons were shown to play a relevant role in determining the electric current in the activity meter.

Updating 90Y Voxel S-Values including internal Bremsstrahlung: Monte Carlo study and development of an analytical model.

PURPOSE: Internal Bremsstrahlung (IB) is a process accompanying ß-decay but neglected in Voxel S-Values (VSVs) calculation. Aims of this work were to calculate, through Monte Carlo (MC) simulation, updated 90Y-VSVs including IB, and to develop an analytical model to evaluate 90Y-VSVs for any voxel size of practical interest. METHODS: GATE (Geant4 Application for Tomographic Emission) was employed for simulating voxelized geometries of soft tissue, with voxels sides l ranging from 2 to 6 mm, in steps of 0.5 mm. The central voxel was set as a homogeneous source of 90Y when IB photons are not modelled. For each l, the VSVs were computed for 90Y decays alone and for 90Y + IB. The analytical model was then built through fitting procedures of the VSVs including IB contribution. RESULTS: Comparing GATE-VSVs with and without IB, differences between + 25% and + 30% were found for distances from the central voxel larger than the maximum ß-range. The analytical model showed an agreement with MC simulations within ± 5% in the central voxel and in the Bremsstrahlung tails, for any l value examined, and relative differences lower than ± 40%, for other distances from the source. CONCLUSIONS: The presented 90Y-VSVs include for the first time the contribution due to IB, thus providing a more accurate set of dosimetric factors for three-dimensional internal dosimetry of 90Y-labelled radiopharmaceuticals and medical devices. Furthermore, the analytical model constitutes an easy and fast alternative approach for 90Y-VSVs estimation for non-standard voxel dimensions.

Internal Bremsstrahlung, the missing process in beta decay Monte Carlo simulation: The relevance in 32P Dose-Point-Kernel estimation.

PURPOSE: In nuclear medicine, Dose Point Kernels (DPKs), representing the energy deposited all around a point isotropic source, are extensively used for dosimetry and are usually obtained by Monte Carlo (MC) simulations. For beta-decaying nuclides, DPK is usually estimated neglecting Internal Bremsstrahlung (IB) emission, a process always accompanying the beta decay and consisting in the emission of photons having a continuous spectral distribution. This work aims to study the significance of IB emission for DPK estimation in the case of 32P and provide DPK values corrected for the IB photon contribution. METHODS: DPK, in terms of the scaled absorbed dose fraction, F(R/X90), was first estimated by GAMOS MC simulation using the standard beta decay spectrum of 32P, Fß(R/X90). Subsequently, an additional source term accounting for IB photons and their spectral distribution was defined and used for a further MC simulation, thus evaluating the contribution of IB emission to DPK values, Fß+IB(R/X90). The relative percent difference, δ, between the DPKs obtained by the two approaches, Fß+IB vs. Fß, was studied as a function of the radial distance, R. RESULTS: As far as the energy deposition is mainly due to the beta particles, IB photons does not significantly contribute to DPK; conversely, for larger R, Fß+IB values are higher by 30-40% than Fß. CONCLUSIONS: The inclusion of IB emission in the MC simulations for DPK estimations is recommended, as well as the use of the DPK values corrected for IB photons, here provided.

18F-PSMA-1007 salivary gland dosimetry: comparison between different methods for dose calculation and assessment of inter- and intra-patient variability.

Objective. Simplified calculation approaches and geometries are usually adopted for salivary glands (SGs) dosimetry. Our aims were (i) to compare different dosimetry methods to calculate SGs absorbed doses (ADs) following [18F]-PSMA-1007 injection, and (ii) to assess the AD variation across patients and single SG components. Approach. Five patients with prostate cancer underwent sequential positron-emission tomography/computed tomography (PET/CT) acquisitions of the head and neck, 0.5, 2 and 4 h after [18F]-PSMA-1007 injection. Parotid and submandibular glands were segmented on CT to derive SGs volumes and masses, while PET images were used to derive Time-Integrated Activity Coefficients. Average ADs to single SG components or total SG (tSG) were calculated with the following methods: (i) direct Monte Carlo simulation with GATE/GEANT4 considering radioactivity in the entire PET/CT field-of-view (MC) or in the SGs only (MCsgo); (ii) spherical model (SM) of OLINDA/EXM 2.1, adopting either patient-specific or standard ICRP89 organ masses (SMstd); (iii) ellipsoidal model (EM); (iv) MIRD approach with organS-factors from OLINDA/EXM 2.1 and OpenDose collaboration, with or without contribution from cross irradiation originating outside the SGs. The maximum percent AD difference across SG components (δmax) and across patients (Δmax) were calculated.Main results. Compared to MC, ADs to single SG components were significantly underestimated by all methods (average relative differences ranging between -11.9% and -30.5%).δmaxvalues were never below 25%. The highestδmax(=702%) was obtained with SMstd. Concerning tSG, results within 10% of the MC were obtained only if cross-irradiation from the remainder of the body or from the remainder of the head was accounted for. The Δmaxranged between 58% and 78% across patients.Significance. Simple geometrical models for SG dosimetry considerably underestimated ADs compared to MC, particularly if neglecting cross-irradiation from neighboring regions. Specific masses of single SG components should always be considered given their large intra- and inter-patient variability.

Technical note: The contribution of internal bremsstrahlung to the 90 Y dose point kernel.

BACKGROUND: Internal dosimetry has an increasing role in the planning and verification of nuclear medicine therapies with radiopharmaceuticals. Dose Point Kernels (DPKs), quantifying the energy deposition all around a point source, in a homogenous medium, are extensively used for 3D dosimetry and nowadays are mostly evaluated by Monte Carlo (MC) simulation. To our knowledge, DPK for beta emitters is estimated neglecting the continuous photon emission due to the Internal Bremsstrahlung (IB), whose contribution to the absorbed dose can be relevant beyond the maximum range of betas, as evidenced in recent works. PURPOSE: Aim of this study was to investigate and quantify, by means of MC simulations, the contribution of IB photons to DPK calculated for 90 Y and provide the updated 90 Y DPK. METHODS: The overall radiation due to the decay of a 90 Y point source, placed at the centre of concentric water shells of increasing radii from 0.02 cm to 20 cm, was simulated with GAMOS, including the IB source term whose spectral distribution was described by an analytical model. Energy deposition was scored in the shells as a function of the distance from the source, R, and DPK was estimated in terms of the scaled absorbed dose fraction, F(R/X90 ), where X90 is the range within which the beta particles deposit 90% of their energy. RESULTS: A comparison between the two simulated absorbed dose distributions, calculated with or without IB, clearly shows that the latter (incomplete) choice is consistent with the findings of other Authors and systematically underestimates the absorbed dose imparted to the tissue. 90 Y DPK values currently used are underestimated by 20%-34% for R>2X90 . CONCLUSIONS: The revised values provided in this work suggest that the inclusion of IB emission in DPK evaluations is advisable for pure beta emitters.

An analytic model to calculate voxel s-values for177Lu.

Objective.177Lu is one of the most employed isotopes in targeted radionuclide therapies and theranostics, and 3D internal dosimetry for such procedures has great importance. Voxel S-Values (VSVs) approach is widely used for this purpose, but VSVs are available for a limited number of voxel dimensions. The aim of this work is to develop an analytic model for the calculation of177Lu-VSVs in any cubic voxelized geometry of practical interest.Approach. Monte Carlo (MC) simulations were implemented with the toolkit GAMOS to evaluate VSVs in voxelized geometries of soft tissue from a source of177Lu homogeneously distributed in the central voxel. Nine geometric setups, containing 15 × 15 × 15 cubic voxels of sideslranging from 2 mm to 6 mm, in steps of 0.5 mm, were considered. For eachl, the VSVs computed as a function of the 'normalized radius',Rn= R/l(withR = distance from the center of the source voxel), were fitted with a parametric function. The dependencies of the parameters as a function oflwere then fitted with appropriate functions, in order to implement the model for deducing177Lu-VSVs for anylwithin the aforementioned range.Main results. The MC-derived VSVs were satisfactorily compared with literature data for validation, and the VSVs computed with the analytic model agree with the MC ones within 2% forRn≤ 2 and within 6% forRn> 2.Significance. The proposed model enables the easy and fast calculation, with a simple spreadsheet, of177Lu-VSVs in any cubic voxelized geometry of practical interest, avoiding the necessity of implementingad-hocMC simulations to estimate VSVs for specific voxel dimensions not available in literature data.

Relevance of artefacts in99mTc-MAA SPECT scans on pre-therapy patient-specific90Y TARE internal dosimetry: a GATE Monte Carlo study.

Objective.The direct Monte Carlo (MC) simulation of radiation transport exploiting morphological and functional tomographic imaging as input data is considered the gold standard for internal dosimetry in nuclear medicine, and it is increasingly used in studies regarding trans-arterial radio-embolization (TARE). However, artefacts affecting the functional scans, such as reconstruction artefacts and motion blurring, decrease the accuracy in defining the radionuclide distribution in the simulations and consequently lead to errors in absorbed dose estimations. In this study, the relevance of such artefacts in patient-specific three-dimensional MC dosimetry was investigated in three cases of90Y TARE.Approach.The pre-therapy99mTc MacroAggregate Albumin (Tc-MAA) SPECTs and CTs of patients were used as input for simulations performed with the GEANT4-based toolkit GATE. Several pre-simulation SPECT-masking techniques were implemented, with the aim of zeroing the decay probability in air, in lungs, or in the whole volume outside the liver.Main results.Increments in absorbed dose up to about +40% with respect to the native-SPECT simulations were found in liver-related volumes of interest (VOIs), depending on the masking procedure adopted. Regarding lungs-related VOIs, decrements in absorbed doses in right lung as high as -90% were retrieved.Significance.These results highlight the relevant influence of SPECT artefacts, if not properly treated, on dosimetric outcomes for90Y TARE cases. Well-designed SPECT-masking techniques appear to be a promising way to correct for such misestimations.

Simplified patient-specific renal dosimetry in 177Lu therapy: a proof of concept.

PURPOSE: The aim of this proof-of-concept study is to propose a simplified personalized kidney dosimetry procedure in 177Lu peptide receptor radionuclide therapy (PRRT) for neuroendocrine tumors and metastatic prostate cancer. It relies on a single quantitative SPECT/CT acquisition and multiple radiometric measurements executed with a collimated external probe, properly directed on kidneys. METHODS: We conducted a phantom study involving external count-rate measurements in an abdominal phantom setup filled with activity concentrations of 99mTc, reproducing patient-relevant organ effective half-lives occurring in 177Lu PRRT. GATE Monte Carlo (MC) simulations of the experiment, using 99mTc and 177Lu as sources, were performed. Furthermore, we tested this method via MC on a clinical case of 177Lu-DOTATATE PRRT with SPECT/CT images at three time points (2, 20 and 70 hrs), comparing a simplified kidney dosimetry, employing a single SPECT/CT and probe measurements at three time points, with the complete MC dosimetry. RESULTS: The experimentally estimated kidney half-life with background subtraction applied was compatible within 3% with the expected value. The MC simulations of the phantom study, both with 99mTc and 177Lu, confirmed a similar level of accuracy. Concerning the clinical case, the simplified dosimetric method led to a kidney dose estimation compatible with the complete MC dosimetry within 6%, 12% and 2%, using respectively the SPECT/CT at 2, 20 and 70 hrs. CONCLUSIONS: The proposed simplified procedure provided a satisfactory accuracy and would reduce the imaging required to derive the kidney absorbed dose to a unique quantitative SPECT/CT, with consequent benefits in terms of clinic workflows and patient comfort.

Relevance of Internal Bremsstrahlung photons from 90Y decay: an experimental and Monte Carlo study.

Internal Bremsstrahlung (IB) is a continuous electromagnetic radiation accompanying beta decay; however, this process is not considered in radiation protection studies, particularly when estimating exposure from beta-decaying radionuclides. The aims of the present work are: i) to show that neglecting the IB process in Monte Carlo (MC) simulation leads to an underestimation of the energy deposited in a ionization chamber, in the case of a high-energy pure beta emitter such as Yttrium-90 (90Y), and ii) to determine the most reliable choice of source term for 90Y IB to be used in MC simulations. For this radionuclide, commonly employed in nuclear medicine and radiochemistry applications, experimental data acquired with a well ionization chamber have been compared with Monte Carlo (MC) calculations carried out in the GAMOS framework. Simulations that do not include the effect of the IB process, are found to give results underestimating the experimental values by 12-14%. Consequently, two models for the IB energy spectra, previously described by Italiano et al. [1], have been implemented using MC simulation and a good agreement has been achieved with one of them. We therefore conclude that inclusion of IB process in Monte Carlo simulation packages is advisable for a more accurate and complete treatment of electromagnetic interactions.

Enhancement of radiation exposure risk from ß-emitter radionuclides due to Internal Bremsstrahlung effect: A Monte Carlo study of 90Y case.

Employment of ß-decaying radionuclides, used in many fields (industrial, clinical, research) requires a correct assessment of the operators' radiological exposure. Usually, in the dosimetric evaluation, the contribution coming from Internal Bremsstrahlung (IB) accompanying the ß-decay is not kept into account; nevertheless, this negligibility does not always appear justified, at least for high-energy ß-emitters. By means of Monte Carlo (MC) simulations, we showed how the contribution from IB photons is noteworthy for the evaluation of the overall radiation absorbed dose in the case of 90Y source. We evaluated an increase of the absorbed doses, respectively for a point source and the considered receptacles, up to + 34% and + 60% or + 15% and + 28%, depending on the adopted model of IB spectrum. These results demonstrate the relevance of IB phenomenon in radiation protection estimations and suggest extending future theoretical and experimental studies to other ß-decaying radionuclides.

Internal dosimetry for TARE therapies by means of GAMOS Monte Carlo simulations.

Three-dimensional internal dosimetry is increasingly used in planning Trans-Arterial Radio-Embolization (TARE) of HepatoCellular Carcinoma (HCC). Among the existing calculation approaches, Monte Carlo (MC) simulation is the gold standard. Aim of this work was to carry out a retrospective study of clinical cases of TARE to compare the performances of different computation approaches. We developed a procedure exploiting GAMOS (GEANT4-based Architecture for Medicine-Oriented Simulations) MC. Three dimensional absorbed dose maps, dose profiles and Dose Volume Histograms (DVHs) were produced for liver through MC simulations and convolution method implemented in STRATOS software. We compared the average absorbed doses with results of Medical International Radiation Dose (MIRD) approach. For most patients, a reasonable agreement was found, with relative differences in mean doses within (-20.2%,+15.6%) for MIRD vs. MC and (-12.1%, +7.6%) for STRATOS vs. MC. Discrepancies can mainly be related to the gamma-rays contribution, more precisely taken into account in MC. For one patient we evaluated through MC simulation a lung dose of about 2 Gy coming from pulmonary shunt (96%) and from irradiation from liver (4%), with values up to 4.5 Gy near liver-lung interface. 3D dosimetry for TARE treatments can be satisfactorily carried out with convolution methods as long as VOIs of regular shape are considered. MC simulations are more appropriate for VOIs where the contribution from gamma-rays has to be carefully taken into account. The absorbed dose distribution in presence of relevant tissue inhomogeneities can be assessed accurately by means of MC simulations only.

Efficacy of Vemurafenib in Patients With Non-Small-Cell Lung Cancer With BRAF V600 Mutation: An Open-Label, Single-Arm Cohort of the Histology-Independent VE-BASKET Study.

PURPOSE: To study whether BRAF V600 mutations in non-small-cell lung cancer (NSCLC) may indicate sensitivity to the BRAF inhibitor vemurafenib, we included a cohort of patients with NSCLC in the vemurafenib basket (VE-BASKET) study. On the basis of observed early clinical activity, we expanded the cohort of patients with NSCLC. We present results from this cohort. METHODS: This open-label, histology-independent, phase II study included six prespecified cohorts, including patients with NSCLC, and a seventh all-comers cohort. Patients received vemurafenib (960 mg two times per day) until disease progression or unacceptable toxicity. The primary end point of the final analysis was objective response rate (Response Evaluation Criteria in Solid Tumors, version 1.1). Secondary end points included progression-free survival, overall survival, and safety. Because the prespecified clinical benefit endpoint was met in the initial NSCLC cohort, the cohort was expanded. RESULTS: Sixty-two patients with BRAF V600-mutant NSCLC were enrolled and treated: 13% (n = 8) had received no prior systemic therapy, and 87% (n = 54) had received prior therapies. The objective response rate was 37.1% (95% CI, 25.2% to 50.3%) overall, 37.5% (95% CI, 8.5% to 75.5%) in previously untreated patients, and 37.0% (24.3% to 51.3%) in previously treated patients. Median progression-free survival was 6.5 months (95% CI, 5.2 to 9.0 months), and median overall survival was 15.4 months (95% CI, 9.6 to 22.8 months). The most common all-grade adverse event was nausea (40%). The safety profile of vemurafenib was similar to that observed in melanoma studies. CONCLUSION: Vemurafenib showed promising activity in patients with NSCLC harboring BRAF V600 mutations. The safety profile of vemurafenib was similar to previous observations in patients with melanoma. Our results suggest a role for single-agent BRAF inhibition in patients with NSCLC and BRAF V600 mutations.

Radiation protection from external exposure to radionuclides: A Monte Carlo data handbook.

The availability of a resource collecting dose factors for the evaluation of the absorbed doses from external exposure during the manipulation of radioactive substances is fundamental for radiological protection purposes. Monte Carlo simulations are useful for the accurate calculation of dose distributions in complex geometries, particularly in presence of extended spectra of multi-radiation sources. We considered, as possible irradiation scenarios, a point source, a uniform planar source resembling a contaminated surface, several source volumes contained in plastic or glass receptacles, and the direct skin contamination case, implementing the corresponding Monte Carlo simulations in GAMOS (GEANT4-based Architecture for Medicine-Oriented Simulations). A set of 50 radionuclides was studied, focusing the attention on those ones mainly used in nuclear medicine, both for diagnostic and therapeutic purposes, in nuclear physics laboratories and for instrument calibration. Skin dose equivalents at 70 µm of depth and deep dose equivalents at 10 mm of depth are reported for different configurations and organized in easy-to-read tables.

Evaluation of skin absorbed doses during manipulation of radioactive sources: a comparison between the VARSKIN code and Monte Carlo simulations.

The evaluation of skin doses during manipulation of radioactive sources can be a critical issue for which the most accurate calculation strategies available should be used. The aim of this work was to compare the results of the analytical approach used in VARSKIN with the simulation of radiation transport and interaction by Monte Carlo calculations in GAMOS (GEANT4-based Architecture for Medicine-Oriented Simulations), and to provide an accurate and versatile tool for the evaluation of skin doses from radionuclide sources of any realistic shape (e.g. cylindrical, parallelepiped), even in the presence of multiple interposed absorber layers. A set of 20 radionuclides (pure ß, ß-γ, Auger and γ emitters) from among the most frequently employed in nuclear medicine and laboratory practices were selected for comparison. We studied a point-like and a cylindrical source, in the presence of varying thicknesses of absorbing layers. We found a general agreement for most nuclides when the source was directly in contact with skin or in the presence of a thin layer of absorbing material. However, when the thickness of the absorber increased, significant differences were found for several nuclides. In these cases, the proposed method based on a dedicated Monte Carlo simulation could give more accurate results in a reasonable time, which could optimise accuracy when assessing skin doses in routine as well as incidental exposure scenarios.

A Monte Carlo approach to small-scale dosimetry of solid tumour microvasculature for nuclear medicine therapies with (223)Ra-, (131)I-, (177)Lu- and (111)In-labelled radiopharmaceuticals.

The small-scale dosimetry of radionuclides in solid-tumours is directly related to the intra-tumoral distribution of the administered radiopharmaceutical, which is affected by its egress from the vasculature and dispersion within the tumour. The aim of the present study was to evaluate the combined dosimetric effects of radiopharmaceutical distribution and range of the emitted radiation in a model of tumour microvasculature. We developed a computational model of solid-tumour microenvironment around a blood capillary vessel, and we simulated the transport of radiation emitted by (223)Ra, (111)In, (131)I and (177)Lu using the GEANT4 Monte Carlo. For each nuclide, several models of radiopharmaceutical dispersion throughout the capillary vessel were considered. Radial dose profiles around the capillary vessel, the Initial Radioactivity (IR) necessary to deposit 100 Gy of dose at the edge of the viable tumour-cell region, the Endothelial Cell Mean Dose (ECMD) and the Tumour Edge Mean Dose (TEMD), i.e. the mean dose imparted at the 250-µm layer of tissue, were computed. The results for beta and Auger emitters demonstrate that the photon dose is about three to four orders of magnitude lower than that deposited by electrons. For (223)Ra, the beta emissions of its progeny deliver a dose about three orders of magnitude lower than that delivered by the alpha emissions. Such results may help to characterize the dose inhomogeneities in solid tumour therapies with radiopharmaceuticals, taking into account the interplay between drug distribution from vasculature and range of ionizing radiations.

An analytical model for calculating internal dose conversion coefficients for non-human biota.

To assess the radiation burden of non-human living organisms, dose coefficients are available in the literature, precalculated by assuming an ellipsoidal shape of each organism. A previously developed analytical method was applied for the determination of absorbed fractions inside ellipsoidal volumes from alpha, beta, and gamma radiations to the calculation of dose conversion coefficients (DCCs) for 15 reference organisms, animals and plants, either terrestrial, amphibian, or aquatic, and six radionuclides ((14)C, (90)Sr, (60)Co, (137)Cs, (238)U, and (241)Am). The results were compared with the reference values reported in Publication 108 of the International Commission on Radiological Protection, in which a different calculation approach for DCCs was employed. The results demonstrate that the present analytical method, originally intended for applications in internal dosimetry of nuclear medicine therapy, gives consistent results for all the beta-, beta-gamma-, and alpha-emitting radionuclides tested in a wide range of organism masses, between 8 mg and 1.3 kg. The applicability of the method proposed can take advantage from its ease of implementation in an ordinary electronic spreadsheet, allowing to calculate, for virtually all possible radionuclide emission spectra, the DCCs for ellipsoidal models of non-human living organisms in the environment.

Absorbed fractions for alpha particles in ellipsoidal volumes.

Internal dosimetry of alpha particles is gaining attention due to the increasing applications in cancer treatment and also for the assessment of environmental contamination from radionuclides. We developed a Monte Carlo simulation in GEANT4 in order to calculate the absorbed fractions for monoenergetic alpha particles in the energy interval between 0.1 and 10 MeV, uniformly distributed in ellipsoids made of soft tissue. For each volume, we simulated a spherical shape, three oblate and three prolate ellipsoids, and one scalene shape. For each energy and for every geometrical configuration, an analytical relationship between the absorbed fraction and a 'generalized radius' was found; and the dependence of the fit parameters on the alpha energy is discussed and fitted by parametric functions. With the proposed formulation, the absorbed fraction for alpha particles in the energy range explored can be calculated for volumes and for ellipsoidal shapes of practical interest. This method can be applied to the evaluation of absorbed fraction from alpha-emitting radionuclides. The contribution to the deposited energy coming from electron and photon emissions can be accounted for exploiting the specific formulations previously introduced. As an example of application, the dosimetry of (213)Bi and its decay chain in ellipsoids is reported.

Monte Carlo study of the dose enhancement effect of gold nanoparticles during X-ray therapies and evaluation of the anti-angiogenic effect on tumour capillary vessels.

Gold nanoparticles (GNPs) are a promising radiosensitizer agent in radiotherapy. Through a simulation performed with the Geant4 Monte Carlo code, we evaluated the dose enhancement effect of GNPs during therapies with an x-ray tube operating at 150 kV (E = 55 keV and E(max) = 150 keV) and we studied the impact of GNP diffusion out of the tumour vessels, in terms of antiangiogenic and cytotoxic effects. Firstly, a single x-ray beam was assumed to irradiate a parallelepiped volume of soft tissue, in which a GNP-doped "target" volume was placed at different depths. Average dose enhancement factors (DEF) in presence of GNPs were obtained as a function of the target depth and GNP concentration, uniformly distributed; values ranging between 1.6 for 10 mg Au/g at 0 cm and 7.2 for 200 mg Au/g at 5 cm were determined. Furtherly, a second geometry was adopted, in which a blood capillary vessel (10 µm thick and 10 µm of inner radius) was placed at the centre of a cubic volume of soft tissue; doses and DEFs to the capillary endothelium as well as to the surrounding viable tumour were evaluated, for different models of GNP diffusion. Our results indicate that the radial DEF profiles around the vessel are in close relationship with the radial profiles of GNP concentration assumed, except for at sharp gradients of concentration. DEFs at the endothelium ranged from 1.6 to 6.5, for GNP concentrations in the blood of 10 and 200 mg/ml, respectively. These data can be helpful for the development of new and more specific GNP-based radiosensitizers of potential interest in radiotherapy, exploiting the combined benefit of anti-angiogenic and cytotoxic dose enhancement effects.