Monte Carlo Track Structure Code Research Articles

Physics and small-scale dosimetry of -emitters for targeted radionuclide therapy: The case of .

Monte Carlo simulations have been considered for a long time the gold standard for dose calculations in conventional radiotherapy and are currently being applied for the same purpose in innovative radiotherapy techniques such as targeted radionuclide therapy (TRT). We present in this work a benchmarking study of the latest version of the Transport d'Ions Lourds Dans l'Aqua & Vivo (TILDA-V) Monte Carlo track structure code, highlighting its capabilities for describing the full slowing down of -particles in water and the energy deposited in cells by -emitters in the context ofTRT. We performed radiation transport simulations of -particles (10keV -100MeV ) in water with TILDA-Vand the Particle and Heavy Ion Transport code System (PHITS) version 3.33. We compared the predictions of each code in terms of track parameters (stopping power, range and radial dose profiles) and cellular S-values of the promising radionuclide astatine-211 ( ). Additional comparisons were made with available data in theliterature. The stopping power, range and radial dose profiles of -particles computed with TILDA-Vwere in excellent agreement with other calculations and available data. Overall, minor differences with PHITS were ascribed to phase effects, that is, related to the use of interaction cross sectionscomputed for water vapor or liquid water. However, important discrepancies were observed in the radial dose profiles of monoenergetic -particles, for which PHITS results showed a large underestimation of the absorbed dose compared to other codes and experimental data. The cellular S-values of computed with TILDA-V agreed within 4% with the values predicted by PHITS andMIRDcell. The validation of the TILDA-Vcode presented in this work opens the possibility to use it as an accurate simulation tool for investigating the interaction of -particles in biological media down to the nanometer scale in the context of medical research. The code may help nuclear medicine physicians in their choice of -emitters for TRT. Further research will focus on the application of TILDA-Vfor quantifying radioinduced damage on the deoxyribonucleic acid (DNA) molecule.

Palladium-103 (103Pd/103mRh), a promising Auger-electron emitter for targeted radionuclide therapy of disseminated tumor cells - absorbed doses in single cells and clusters, with comparison to 177Lu and 161Tb.

Early use of targeted radionuclide therapy (TRT) to eradicate disseminated tumor cells (DTCs) might offer cure. Selection of appropriate radionuclides is required. This work highlights the potential of 103Pd (T1/2 = 16.991 d) which decays to 103mRh (T1/2 = 56.12 min) then to stable 103Rh with emission of Auger and conversion electrons. Methods: The Monte Carlo track structure code CELLDOSE was used to assess absorbed doses in single cells (14-μm diameter; 10-μm nucleus) and clusters of 19 cells. The radionuclide was distributed on the cell surface, within the cytoplasm, or in the nucleus. Absorbed doses from 103Pd, 177Lu and 161Tb were compared after energy normalization. The impact of non-uniform cell targeting, and the potential benefit from dual-targeting was investigated. Additional results related to 103mRh, if used directly, are provided. Results: In the single cell, and depending on radionuclide distribution, 103Pd delivered 7- to 10-fold higher nuclear absorbed dose and 9- to 25-fold higher membrane dose than 177Lu. In the 19-cell clusters, 103Pd absorbed doses also largely exceeded 177Lu. In both situations, 161Tb stood in-between 103Pd and 177Lu. Non-uniform targeting, considering four unlabeled cells within the cluster, resulted in moderate-to-severe dose heterogeneity. For example, with intranuclear 103Pd, unlabeled cells received only 14% of the expected nuclear dose. Targeting with two 103Pd-labeled radiopharmaceuticals minimized dose heterogeneity. Conclusion: 103Pd, a next-generation Auger emitter, can deliver substantially higher absorbed doses than 177Lu to single tumor cells and cell clusters. This may open new horizons for the use of TRT in adjuvant or neoadjuvant settings, or for targeting minimal residual disease.

Experimental validation in a neutron exposure frame of the MINAS TIRITH for cell damage simulation

In the domains of medicine and space exploration, refining risk assessment models for protecting healthy tissue from ionizing radiation is crucial. Understanding radiation-induced effects requires biological experimentations at the cellular population level and the cellular scale modeling using Monte Carlo track structure codes. We present MINAS TIRITH, a tool using Geant4-DNA Monte Carlo-generated databases to study DNA damage distribution at the cell population scale. It introduces a DNA damage location module and proposes a method to convert double-strand breaks (DSB) into DNA Damage Response foci. We evaluate damage location precision and DSB-foci conversion parameters. MINAS TIRITH’s accuracy is validated against γ-H2AX foci distribution from cell population exposed to monoenergetic neutron beams (2.5 or 15.1 MeV) under different configurations, yielding mixed radiation fields. Strong agreement between simulation and experimental results was found demonstrating MINAS TIRITH’s predictive precision in radiation-induced DNA damage topology. Additionally, modeling intercellular damage variability within a population subjected to a specific macroscopic dose identifies subpopulations, enhancing realistic fate models. This approach advances our understanding of radiation-induced effects on cellular systems for risk assessment improvement.

An Analytical Method for Quantifying the Yields of DNA Double-Strand Breaks Coupled with Strand Breaks by γ-H2AX Focus Formation Assay Based on Track-Structure Simulation.

Complex DNA double-strand break (DSB), which is defined as a DSB coupled with additional strand breaks within 10 bp in this study, induced after ionizing radiation or X-rays, is recognized as fatal damage which can induce cell death with a certain probability. In general, a DSB site inside the nucleus of live cells can be experimentally detected using the γ-H2AX focus formation assay. DSB complexity is believed to be detected by analyzing the focus size using such an assay. However, the relationship between focus size and DSB complexity remains uncertain. In this study, using Monte Carlo (MC) track-structure simulation codes, i.e., an in-house WLTrack code and a Particle and Heavy Ion Transport code System (PHITS), we developed an analytical method for qualifying the DSB complexity induced by photon irradiation from the microscopic image of γ-H2AX foci. First, assuming that events (i.e., ionization and excitation) potentially induce DNA strand breaks, we scored the number of events in a water cube (5.03 × 5.03 × 5.03 nm3) along electron tracks. Second, we obtained the relationship between the number of events and the foci size experimentally measured by the γ-H2AX focus formation assay. Third, using this relationship, we evaluated the degree of DSB complexity induced after photon irradiation for various X-ray spectra using the foci size, and the experimental DSB complexity was compared to the results estimated by the well-verified DNA damage estimation model in the PHITS code. The number of events in a water cube was found to be proportional to foci size, suggesting that the number of events intrinsically related to DSB complexity at the DNA scale. The developed method was applicable to focus data measured for various X-ray spectral situations (i.e., diagnostic kV X-rays and therapeutic MV X-rays). This method would contribute to a precise understanding of the early biological impacts of photon irradiation by means of the γ-H2AX focus formation assay.

Modeling of DNA Damage Repair and Cell Response in Relation to p53 System Exposed to Ionizing Radiation.

Repair of DNA damage induced by ionizing radiation plays an important role in the cell response to ionizing radiation. Radiation-induced DNA damage also activates the p53 system, which determines the fate of cells. The kinetics of repair, which is affected by the cell itself and the complexity of DNA damage, influences the cell response and fate via affecting the p53 system. To mechanistically study the influences of the cell response to different LET radiations, we introduce a new repair module and a p53 system model with NASIC, a Monte Carlo track structure code. The factors determining the kinetics of the double-strand break (DSB) repair are modeled, including the chromosome environment and complexity of DSB. The kinetics of DSB repair is modeled considering the resection-dependent and resection-independent compartments. The p53 system is modeled by simulating the interactions among genes and proteins. With this model, the cell responses to low- and high-LET irradiation are simulated, respectively. It is found that the kinetics of DSB repair greatly affects the cell fate and later biological effects. A large number of DSBs and a slow repair process lead to severe biological consequences. High-LET radiation induces more complex DSBs, which can be repaired by slow processes, subsequently resulting in a longer cycle arrest and, furthermore, apoptosis and more secreting of TGFβ. The Monte Carlo track structure simulation with a more realistic repair module and the p53 system model developed in this study can expand the functions of the NASIC code in simulating mechanical radiobiological effects.

New damage model for simulating radiation-induced direct damage to biomolecular systems and experimental validation using pBR322 plasmid

In this work, we proposed a new damage model for estimating radiation-induced direct damage to biomolecular systems and validated its the effectiveness for pBR322 plasmids. The proposed model estimates radiation-induced damage to biomolecular systems by: (1) simulation geometry modeling using the coarse-grained (CG) technique to replace the minimum repeating units of a molecule with a single bead, (2) approximation of the threshold energy for radiation damage through CG potential calculation, (3) calculation of cumulative absorption energy for each radiation event in microscopic regions of CG models using the Monte Carlo track structure (MCTS) code, and (4) estimation of direct radiation damage to biomolecular systems by comparing CG potentials and absorption energy. The proposed model replicated measured data with an average error of approximately 14.2% in the estimation of radiation damage to pBR322 plasmids using the common MCTS code Geant4-DNA. This is similar to the results of previous simulation studies. However, in existing damage models, parameters are adjusted based on experimental data to increase the reliability of simulation results, whereas in the proposed model, they can be determined without using empirical data. Because the proposed model proposed is applicable to DNA and various biomolecular systems with minimal experimental data, it provides a new method that is convenient and effective for predicting damage in living organisms caused by radiation exposure.

A model for Geant4-DNA to simulate ionization and excitation of liquid water by protons travelling above 100 MeV

Biological damage induced by ionizing radiation plays a major role in many application fields as radiotherapy and microdosimetry. Geant4-DNA Monte Carlo track-structure code has the capability to simulate the passage of radiation through liquid water, containing physical, physicochemical and chemical processes that lead the early DNA damage. For proton projectile, current models reach up to an incident energy of 100 MeV. In order to cover the entire energy regime involved in proton radiotherapy, this work presents a new model that extends proton ionization and excitation of liquid water up to 300 MeV. Calculation of cross section dataset is made for ionization of five ionization shells and five excitation levels of liquid water using the Relativistic Plane Wave Born Approximation (RPWBA). Implementation is validated through the spower and range examples of the official release, obtaining an agreement within 1% with respect to reference data published in ICRU90 report.

Inelastic scattering of electrons in water from first principles: cross sections and inelastic mean free path for use in Monte Carlo track-structure simulations of biological damage.

Modelling the inelastic scattering of electrons in water is fundamental, given their crucial role in biological damage. In Monte Carlo track-structure (MC-TS) codes used to assess biological damage, the energy loss function (ELF), from which cross sections are extracted, is derived from different semi-empirical optical models. Only recently have first ab initio results for the ELF and cross sections in water become available. For benchmarking purpose, in this work, we present ab initio linear-response time-dependent density functional theory calculations of the ELF of liquid water. We calculated the inelastic scattering cross sections, inelastic mean free paths, and electronic stopping power and compared our results with recent calculations and experimental data showing a good agreement. In addition, we provide an in-depth analysis of the contributions of different molecular orbitals, species and orbital angular momenta to the total ELF. Moreover, we present single-differential cross sections computed for each molecular orbital channel, which should prove useful for MC-TS simulations.

Monte Carlo simulations of nanodosimetry and radiolytic species production for monoenergetic proton and electron beams: Benchmarking of GEANT4-DNA and LPCHEM codes.

In hadrontherapy, biophysical models can be used to predict the biological effect received by cancerous tissues and organs at risk. The input data of these models generally consist of information on nano/micro dosimetric quantities and, concerning some models, reactive species produced in water radiolysis. In order to fully account for the radiation stochastic effects, these input data have to be provided by Monte Carlo track structure (MCTS) codes allowing to estimate physical, physico-chemical, and chemical effects of radiation at the molecular scale. The objective of this study is to benchmark two MCTS codes, Geant4-DNA and LPCHEM, that are useful codes for estimating the biological effects of ions during radiation therapy treatments. In this study we considered the simulation of specific energy spectra for monoenergetic proton beams (10 MeV) as well as radiolysis species production for both electron (1 MeV) and proton (10 MeV) beams with Geant4-DNA and LPCHEM codes. Options 2, 4, and 6 of the Geant4-DNA physics lists have been benchmarked against LPCHEM. We compared probability distributions of energy transfer points in cylindrical nanometric targets (10nm) positioned in a liquid water box. Then, radiochemical species (· OH, , , H2 , and yields simulated between 10-12 and 10-6 s after irradiation are compared. Overall, the specific energy spectra and the chemical yields obtained by the two codes are in good agreement considering the uncertainties on experimental data used to calibrate the parameters of the MCTS codes. For 10 MeV proton beams, ionization and excitation processes are the major contributors to the specific energy deposition (larger than 90%) while attachment, solvation, and vibration processes are minor contributors. LPCHEM simulates tracks with slightly more concentrated energy depositions than Geant4-DNA which translates into slightly faster recombination than Geant4-DNA. Relative deviations (CEV ) with respect to the average of evolution rates of the radical yields between 10-12 and 10-6 s remain below 10%. When comparing execution times between the codes, we showed that LPCHEM is faster than Geant4-DNA by a factor of about four for 1000 primary particles in all simulation stages (physical, physico-chemical, and chemical). In multi-thread mode (four threads), Geant4-DNA computing times are reduced but remain slower than LPCHEM by ∼20% up to ∼50%. For the first time, the entire physical, physico-chemical, and chemical models of two track structure Monte Carlo codes have been benchmarked along with an extensive analysis on the effects on the water radiolysis simulation. This study opens up new perspectives in using specific energy distributions and radiolytic species yields from monoenergetic ions in biophysical models integrated to Monte Carlo software.

Impact of Radiation Quality on Microdosimetry and Chromosome Aberrations for High-Energy (>250 MeV/n) Ions

Studying energy deposition by space radiation at the cellular scale provides insights on health risks to astronauts. Using the Monte Carlo track structure code RITRACKS, and the chromosome aberrations code RITCARD, we performed a modeling study of single-ion energy deposition spectra and chromosome aberrations for high-energy (>250 MeV/n) ion beams with linear energy transfer (LET) varying from 0.22 to 149.2 keV/µm. The calculations were performed using cells irradiated directly by mono-energetic ion beams, and by poly-energetic beams after particle transport in a digital mouse model, representing the radiation exposure of a cell in a tissue. To discriminate events from ion tracks directly traversing the nucleus, to events from δ-electrons emitted by distant ion tracks, we categorized ion contributions to microdosimetry or chromosome aberrations into direct and indirect contributions, respectively. The ions were either ions of the mono-energetic beam or secondary ions created in the digital mouse due to interaction of the beam with tissues. For microdosimetry, the indirect contribution is largely independent of the beam LET and minimally impacted by the beam interactions in mice. In contrast, the direct contribution is strongly dependent on the beam LET and shows increased probabilities of having low and high-energy deposition events when considering beam transport. Regarding chromosome aberrations, the indirect contribution induces a small number of simple exchanges, and a negligible number of complex exchanges. The direct contribution is responsible for most simple and complex exchanges. The complex exchanges are significantly increased for some low-LET ion beams when considering beam transport.

DNA damage modeled with Geant4-DNA: effects of plasmid DNA conformation and experimental conditions

The chemical stage of the Monte Carlo track-structure (MCTS) code Geant4-DNA was extended for its use in DNA strand break (SB) simulations and compared against published experimental data. Geant4-DNA simulations were performed using pUC19 plasmids (2686 base pairs) in a buffered solution of DMSO irradiated by 60Co or 137Cs γ-rays. A comprehensive evaluation of SSB yields was performed considering DMSO, DNA concentration, dose and plasmid supercoiling. The latter was measured using the super helix density value used in a Brownian dynamics plasmid generation algorithm. The Geant4-DNA implementation of the independent reaction times method (IRT), developed to simulate the reaction kinetics of radiochemical species, allowed to score the fraction of supercoiled, relaxed and linearized plasmid fractions as a function of the absorbed dose. The percentage of the number of SB after •OH + DNA and H• + DNA reactions, referred as SSB efficiency, obtained using MCTS were 13.77% and 0.74% respectively. This is in reasonable agreement with published values of 12% and 0.8%. The SSB yields as a function of DMSO concentration, DNA concentration and super helix density recreated the expected published experimental behaviors within 5%, one standard deviation. The dose response of SSB and DSB yields agreed with published measurements within 5%, one standard deviation. We demonstrated that the developed extension of IRT in Geant4-DNA, facilitated the reproduction of experimental conditions. Furthermore, its calculations were strongly in agreement with experimental data. These two facts will facilitate the use of this extension in future radiobiological applications, aiding the study of DNA damage mechanisms with a high level of detail.

Monte Carlo simulations of energy deposition and DNA damage using TOPAS-nBio

Purpose. Monte Carlo (MC) track structure codes are commonly used for predicting energy deposition and radiation-induced DNA damage at the nanometer scale. Various simulation parameters such as physics model, DNA model, and direct damage threshold have been developed. The differences in adopted parameters lead to disparity in calculation results, which requires quantitative evaluation. Methods. Three simulation configurations were implemented in TOPAS-nBio MC toolkit to investigate the impact of physics models, DNA model, and direct damage threshold on the prediction of energy deposition and DNA damage. Dose point kernels (DPKs) of electrons and nanometer-sized volumes irradiated with electrons, protons, and alpha particles were utilized to evaluate the impact of physics models on energy deposition. Proton irradiation of plasmid DNA was used to investigate the disparity in single-strand break and double-strand break (DSB) yields caused by differences in physics models, DNA models, and direct damage thresholds. Results. Electron DPKs obtained with different physics models show similar trends but different diffusiveness and maximums. Energy deposition distributions in nanometer-sized volumes irradiated with electrons, protons, and alpha particles calculated using different physics models have the same trend although discrepancies can be observed at the lowest and highest energy deposits. Strand breaks from incident protons in DNA plasmids vary with adopted parameters. For the configurations in this study, changing physics model, DNA model, and direct damage threshold can cause differences of up to 57%, 69%, and 15% in DSB yields, respectively. All these simulation results are essentially in agreement with previously published simulation or experimental studies. Conclusion. All the physics models, DNA models, and direct damage thresholds investigated in this study are applicable to predict energy deposition and DNA damage. Although the choice of parameters can lead to disparity in simulation results, which serves as a reference for future studies.

Oxygen depletion in FLASH ultra-high-dose-rate radiotherapy: A molecular dynamics simulation.

We present a first-principles molecular dynamics (MD) simulation and expound upon a mechanism of oxygen depletion hypothesis to explain the mitigation of normal tissue injury observed in ultra-high-dose-rate (UHDR) FLASH radiotherapy. We simulated damage to a segment of DNA (also representing other biomolecules such as RNA and proteins) in a simulation box filled with O and molecules. Attoseconds physical interactions (ionizations, electronic, and vibrational excitations) were simulated by using the Monte Carlo track structure code Geant4-DNA. Immediately after ionization, ab initio Car-Parrinello molecular dynamics (CPMD) simulation was used to identify which O and molecules surrounding the DNA molecule were converted into reactive oxygen species (ROS). Subsequently, the femto- to nanosecond reactions of ROS were simulated by using MD with reactive force field (ReaxFF), to illustrate ROS merging into new types of non-reactive oxygen species (NROS) due to strong coupling among ROS. A coarse-grained model was constructed to describe the relevant collective phenomenon at the macroscopic level on ROS aggregation and formation of NROS agglomerates consistent with the underlying microscopic pathways obtained from MD simulations. Time-dependent molecular simulations revealed the formation of metastable and transient spaghetti-like complexes among ROS generated at UHDR. At the higher ROS densities produced under UHDR, stranded chains (i.e., NROS) are produced, mediated through attractive electric polarity forces, hydrogen bonds, and magnetic dipole-dipole interactions among hydroxyl radicals. NROS tend to be less mobile than cellular biomolecules as opposed to the isolated and sparsely dense ROS generated at conventional dose rates (CDR). We attribute this effect to the suppression of biomolecular damage induced per particle track. At a given oxygen level, as the dose rate increases, the size and number of NROS chains increase, and correspondingly the population of toxic ROS components decreases. Similarly, at a given high dose rate, as the oxygen level increases, so do the size and number of NROS chains until an optimum level of oxygen is reached. Beyond that level, the amount of oxygen present may be sufficient to saturate the production of NROS chains, thereby reversing the sparing effects of UHDRs. We showed that oxygen depletion, hypothesized to lead to lower normal-tissue toxicity at FLASH dose rates, takes place within femto- to nanoseconds after irradiation. The mechanism is governed by the slow dynamics of chains of ROS complexes (NROS). Under physoxic (≈ 4-5% oxygen) conditions (i.e., in normal tissues), NROS are more abundant than in hypoxic conditions (e.g., <0.3% in parts of tumors), suggesting that biomolecular damage would be reduced in an environment with physoxic oxygen levels. Hence irradiation at UHDRs would be more effective for sparing physoxic normal tissues but not tumors containing regions of hypoxia. At much higher levels of oxygen (e.g., >10-15%), oxygen depletion by UHDRs may not be sufficient for tissue sparing.

LET-Dependent Intertrack Yields in Proton Irradiation at Ultra-High Dose Rates Relevant for FLASH Therapy.

FLASH radiotherapy delivers a high dose (≥10 Gy) at a high rate (≥40 Gy/s). In this way, particles are delivered in pulses as short as a few nanoseconds. At that rate, intertrack reactions between chemical species produced within the same pulse may affect the heterogeneous chemistry stage of water radiolysis. This stochastic process suits the capabilities of the Monte Carlo method, which can model intertrack effects to aid in radiobiology research, including the design and interpretation of experiments. In this work, the TOPAS-nBio Monte Carlo track-structure code was expanded to allow simulations of intertrack effects in the chemical stage of water radiolysis. Simulation of the behavior of radiolytic yields over a long period of time (up to 50 s) was verified by simulating radiolysis in a Fricke dosimeter irradiated by 60Co γ rays. In addition, LET-dependent G values of protons delivered in single squared pulses of widths, 1 ns, 1 µs and 10 µs, were obtained and compared to simulations using no intertrack considerations. The Fricke simulation for the calculated G value of Fe3+ ion at 50 s was within 0.4% of the accepted value from ICRU Report 34. For LET-dependent G values at the end of the chemical stage, intertrack effects were significant at LET values below 2 keV/µm. Above 2 keV/µm the reaction kinetics remained limited locally within each track and thus, effects of intertrack reactions remained low. Therefore, when track structure simulations are used to investigate the biological damage of FLASH irradiation, these intertrack reactions should be considered. The TOPAS-nBio framework with the expansion to intertrack chemistry simulation provides a useful tool to assist in this task.

Radiation doses from 161Tb and 177Lu in single tumour cells and micrometastases

BackgroundTargeted radionuclide therapy (TRT) is gaining importance. For TRT to be also used as adjuvant therapy or for treating minimal residual disease, there is a need to increase the radiation dose to small tumours. The aim of this in silico study was to compare the performances of 161Tb (a medium-energy β− emitter with additional Auger and conversion electron emissions) and 177Lu for irradiating single tumour cells and micrometastases, with various distributions of the radionuclide.MethodsWe used the Monte Carlo track-structure (MCTS) code CELLDOSE to compute the radiation doses delivered by 161Tb and 177Lu to single cells (14 μm cell diameter with 10 μm nucleus diameter) and to a tumour cluster consisting of a central cell surrounded by two layers of cells (18 neighbours). We focused the analysis on the absorbed dose to the nucleus of the single tumoral cell and to the nuclei of the cells in the cluster. For both radionuclides, the simulations were run assuming that 1 MeV was released per μm3 (1436 MeV/cell). We considered various distributions of the radionuclides: either at the cell surface, intracytoplasmic or intranuclear.ResultsFor the single cell, the dose to the nucleus was substantially higher with 161Tb compared to 177Lu, regardless of the radionuclide distribution: 5.0 Gy vs. 1.9 Gy in the case of cell surface distribution; 8.3 Gy vs. 3.0 Gy for intracytoplasmic distribution; and 38.6 Gy vs. 10.7 Gy for intranuclear location. With the addition of the neighbouring cells, the radiation doses increased, but remained consistently higher for 161Tb compared to 177Lu. For example, the dose to the nucleus of the central cell of the cluster was 15.1 Gy for 161Tb and 7.2 Gy for 177Lu in the case of cell surface distribution of the radionuclide, 17.9 Gy for 161Tb and 8.3 Gy for 177Lu for intracytoplasmic distribution and 47.8 Gy for 161Tb and 15.7 Gy for 177Lu in the case of intranuclear location.Conclusion161Tb should be a better candidate than 177Lu for irradiating single tumour cells and micrometastases, regardless of the radionuclide distribution.

Simulation of single cell irradiation by proton beams using TILDA-V

SynopsisThe purpose of the present work is to emphasize the need for realistic modeling of the biological medium when studying the transport of protons in living matter at the very small scale. In this context, we have used the TILDA-V Monte Carlo track-structure code to simulate the irradiation of single cells with proton beams over the energy range of 10 keV – 100 MeV.

Proton transport modeling in a realistic biological environment by using TILDA-V

Whether it is in radiobiology to identify DNA lesions or in medicine to adapt the radiotherapeutic protocols, a detailed understanding of the radiation-induced interactions in living matter is required. Monte Carlo track-structure codes have been successfully developed to describe these interactions and predict the radiation-induced energy deposits at the nanoscale level in the medium of interest. In this work, the quantum-mechanically based Monte Carlo track-structure code TILDA-V has been used to compute the slowing-down of protons in water and DNA. Stopping power and range are then reported and compared with existing data. Then, a first application of TILDA-V to cellular irradiations is also reported in order to highlight the absolute necessity of taking into account a realistic description of the cellular environment in microdosimetry.

Evaluation of the influence of physical and chemical parameters on water radiolysis simulations under MeV electron irradiation using Geant4-DNA

This paper presents the influence of electron elastic scattering models, electron thermalization models, and chemical parameters on Geant4-DNA simulations of liquid water radiolysis under mega-electron-volt electron irradiation. The radiochemical yields are simulated using a new Geant4-DNA example. In particular, the influence of the new elastic scattering model recently developed is presented as well as the influence of improved electron thermalization models. The influence of a new chemistry constructor using parameters of another Monte Carlo track structure code is also described. The results calculated using these different models are compared with each other and with experimental data. For sub-mega-electron-volt electron simulations, the combination of the “G4EmDNAPhysics_option2” physics constructor with the recently developed elastic scattering model, the Meesungnoen electron thermalization model, and the “G4EmDNAChemistry_option1” chemistry constructor is recommended.

A cell-by-cell Monte Carlo simulation for assessing radiation-induced DNA double strand breaks

This paper presents a cell-by-cell Monte Carlo simulation study that combines charged particle track structure data with an interphase cell nucleus model to quantify DNA double strand breaks (DSBs), spatial distribution of DSBs in a cell nucleus, and resulting potentially lethal or mutagenic events (PLMEs) between DSBs in close proximity. Cell nucleus is simulated according to the chromosome territory-interchromatin compartment (CT-IC) model in that chromatin content is unevenly distributed in chromatin domains (CDs) and IC with a chromatin compaction ratio of 22:1. A particle track structure coordinate (PTSC) library was first generated for each particle type, energy, and dose based on a large number of particle track data obtained by running the Monte Carlo track structure code Geant4-DNA. To assess the DNA DSBs of a cell for a specific particle type, energy, and dose, the corresponding PTSC was selected and “map overlaid” onto 960 unique cell nucleus data sets containing chromatin fiber (CF) locations. Clustering algorithm DBSCAN was next used to identify the clustered energy deposition events occurring inside the CF. These events were then converted to DNA DSBs using a probabilistic approach. The locations of the DSBs thus obtained were, in turn, used to calculate PLMEs within the cell nucleus that can result from DSB proximity and complexity. The results obtained from this simulation study are correctly correlated to the experimental data of DSB yield and the RBE-LET relationships for various types of charged particles and of various energies. The results show agreement with other published radiobiological models.

Target Size Variation in Microdosimetric Distributions and its Impact on the Linear-Quadratic Parameterization of Cell Survival.

The linear-quadratic (LQ) parameterization of survival fraction [SF( D)] inherently assumes that all cells in a population receive the same dose ( D), albeit the distribution of specific energy z over the individual cells f( z, D) can be very wide. From these microdosimetric distributions, which are target size dependent, we estimate the size of the cellular sensitive volume by analyzing its influence on the LQ parameterization of cell survival. A Monte Carlo track structure code was used to simulate detailed tracks from a 60Co source as well as proton and carbon ions of various energies. From these tracks, f( z, D) distributions were calculated for spherical targets with diameters ranging from 10 nm to 12 μm. A cell survival function based on f( z, D) was fitted to experimental LQ α values, revealing an intrinsic limitation that target size imposes on the usage of f( z, D) to describe the linear term of the LQ parameterization. The results indicate that such threshold volume arises naturally from the relationship between the particle's probability of no-hit and the probability of cell survival. Further analysis led to the proposal of a radiobiological property [Formula: see text], defined as the mean lineal energy corresponding to the target size that allows equivalence between the mean inactivation dose (MID) and the mean specific energy [Formula: see text]. The fact that [Formula: see text] is an increasing continuous function of target size within the range of biological targets of interest in radiobiology, ensures the uniqueness of [Formula: see text] for any radiation quality, thus, its potential usefulness in modeling. In conclusion, an accurate estimation of such threshold volumes may be useful for improving modeling of cell survival curves.