Physics and small-scale dosimetry of α $\alpha$ -emitters for targeted radionuclide therapy: The case of 211 At $

BACKGROUND: 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). PURPOSE: 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 α $\alpha$ -particles in water and the energy deposited in cells by α $\alpha$ -emitters in the context of TRT. METHODS: We performed radiation transport simulations of α $\alpha$ -particles (10 keV u - 1 ${\rm u}^{-1}$ -100 MeV u - 1 ${\rm u}^{-1}$ ) in water with TILDA-V and 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 ( 211 At $^{211}{\rm At}$ ). Additional comparisons were made with available data in the literature. RESULTS: The stopping power, range and radial dose profiles of α $\alpha$ -particles computed with TILDA-V were 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 sections computed for water vapor or liquid water. However, important discrepancies were observed in the radial dose profiles of monoenergetic α $\alpha$ -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 211 At $^{211}{\rm At}$ computed with TILDA-V  agreed within 4% with the values predicted by PHITS and MIRDcell. CONCLUSIONS: The validation of the TILDA-V code presented in this work opens the possibility to use it as an accurate simulation tool for investigating the interaction of α $\alpha$ -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 α $\alpha$ -emitters for TRT. Further research will focus on the application of TILDA-V for quantifying radioinduced damage on the deoxyribonucleic acid (DNA) molecule.

Triply differential cross sections for electron and positron impact on methane.

We here report theoretical triply differential cross sections (TDCS) for 250 eV electron and positron impact ionization of the methane molecule calculated within the second-order distorted-wave Born approximation (DWBA2) for various momentum transfer conditions. The experimental data taken from Isik et al. [J. Phys. B: At., Mol. Opt. Phys. 49, 065203 (2016)] will be compared with the current theoretical predictions as well as molecular three body distorted wave (M3DW) approximation and generalized Sturmian function (GSF) theoretical models in a non-coplanar geometry. In the low analyzer scattering plane, the results obtained within the DWBA2 theory show better agreement with the experimental results compared to the GSF results. The M3DW results also exhibit agreement with the experimental results, in particular in the perpendicular plane geometry. Furthermore, significant differences between electron and positron TDCS were observed.

Membrane and Nuclear Absorbed Doses from 177Lu and 161Tb in Tumor Clusters: Effect of Cellular Heterogeneity and Potential Benefit of Dual Targeting-A Monte Carlo Study.

Early use of targeted radionuclide therapy to eradicate tumor cell clusters and micrometastases might offer cure. However, there is a need to select appropriate radionuclides and assess the potential impact of heterogeneous targeting. Methods: The Monte Carlo code CELLDOSE was used to assess membrane and nuclear absorbed doses from 177Lu and 161Tb (ß--emitter with additional conversion and Auger electrons) in a cluster of 19 cells (14-µm diameter, 10-µm nucleus). The radionuclide distributions considered were cell surface, intracytoplasmic, or intranuclear, with 1,436 MeV released per labeled cell. To model heterogeneous targeting, 4 of the 19 cells were unlabeled, their position being stochastically determined. We simulated situations of single targeting, as well as dual targeting, with the 2 radiopharmaceuticals aiming at different targets. Results: 161Tb delivered 2- to 6-fold higher absorbed doses to cell membranes and 2- to 3-fold higher nuclear doses than 177Lu. When all 19 cells were targeted, membrane and nuclear absorbed doses were dependent mainly on radionuclide location. With cell surface location, membrane absorbed doses were substantially higher than nuclear absorbed doses, both with 177Lu (38-41 vs. 4.7-7.2 Gy) and with 161Tb (237-244 vs. 9.8-15.1 Gy). However, when 4 cells were not targeted by the cell surface radiopharmaceutical, the membranes of these cells received on average only 9.6% of the 177Lu absorbed dose and 2.9% of the 161Tb dose, compared with a cluster with uniform cell targeting, whereas the impact on nuclear absorbed doses was moderate. With an intranuclear radionuclide location, the nuclei of unlabeled cells received only 17% of the 177Lu absorbed dose and 10.8% of the 161Tb dose, compared with situations with uniform targeting. With an intracytoplasmic location, nuclear and membrane absorbed doses to unlabeled cells were one half to one quarter those obtained with uniform targeting, both for 177Lu and for 161Tb. Dual targeting was beneficial in minimizing absorbed dose heterogeneities. Conclusion: To eradicate tumor cell clusters, 161Tb may be a better candidate than 177Lu. Heterogeneous cell targeting can lead to substantial heterogeneities in absorbed doses. Dual targeting was helpful in reducing dose heterogeneity and should be explored in preclinical and clinical studies.

How to explain the sensitivity of DNA double-strand breaks yield to 125I position?

PURPOSE: Auger emitters exhibit interesting features due to their emission of a cascade of short-range Auger electrons. Maximum DNA breakage efficacy is achieved when decays occur near DNA. Studies of double-strand breaks (DSBs) yields in plasmids revealed cutoff distances from DNA axis of 10.5 Å-12 Å, beyond which the mechanism of DSBs moves from direct to indirect effects, and the yield decreases rapidly. Some authors suggested that the average energy deposited in a DNA cylinder could explain such cutoffs. We aimed to study this hypothesis in further detail. MATERIALS AND METHODS: Using the Monte Carlo code CELLDOSE, we investigated the influence of the 125I atom position on energy deposits and absorbed doses per decay not only in a DNA cylinder, but also in individual strands, each modeled as 10 spheres encompassing the fragility sites for phosphodiester bond cleavage. RESULTS: The dose per decay decreased much more rapidly for a sphere in the proximal strand than for the DNA cylinder. For example, when moving the 125I source from 10.5 Å to 11.5 Å, the average dose to the sphere dropped by 43%, compared to only 13% in the case of the cylinder. CONCLUSIONS: Explaining variations in DSBs yields with 125I position should consider the probability of inducing damage in the proximal strand (nearest to the 125I atom). The energy received by fragility sites in this strand is highly influenced by the isotropic (4π) emission of 125I low-energy Auger electrons. The positioning of Auger emitters for targeted radionuclide therapy can be envisioned accordingly.

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

BACKGROUND: Targeted 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 ß- emitter with additional Auger and conversion electron emissions) and 177Lu for irradiating single tumour cells and micrometastases, with various distributions of the radionuclide. METHODS: We 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. RESULTS: For 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. CONCLUSION: 161Tb should be a better candidate than 177Lu for irradiating single tumour cells and micrometastases, regardless of the radionuclide distribution.

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.

Investigation on the correlation between energy deposition and clustered DNA damage induced by low-energy electrons.

This study presents the correlation between energy deposition and clustered DNA damage, based on a Monte Carlo simulation of the spectrum of direct DNA damage induced by low-energy electrons including the dissociative electron attachment. Clustered DNA damage is classified as simple and complex in terms of the combination of single-strand breaks (SSBs) or double-strand breaks (DSBs) and adjacent base damage (BD). The results show that the energy depositions associated with about 90% of total clustered DNA damage are below 150 eV. The simple clustered DNA damage, which is constituted of the combination of SSBs and adjacent BD, is dominant, accounting for 90% of all clustered DNA damage, and the spectra of the energy depositions correlating with them are similar for different primary energies. One type of simple clustered DNA damage is the combination of a SSB and 1-5 BD, which is denoted as SSB + BD. The average contribution of SSB + BD to total simple clustered DNA damage reaches up to about 84% for the considered primary energies. In all forms of SSB + BD, the SSB + BD including only one base damage is dominant (above 80%). In addition, for the considered primary energies, there is no obvious difference between the average energy depositions for a fixed complexity of SSB + BD determined by the number of base damage, but average energy depositions increase with the complexity of SSB + BD. In the complex clustered DNA damage constituted by the combination of DSBs and BD around them, a relatively simple type is a DSB combining adjacent BD, marked as DSB + BD, and it is of substantial contribution (on average up to about 82%). The spectrum of DSB + BD is given mainly by the DSB in combination with different numbers of base damage, from 1 to 5. For the considered primary energies, the DSB combined with only one base damage contributes about 83% of total DSB + BD, and the average energy deposition is about 106 eV. However, the energy deposition increases with the complexity of clustered DNA damage, and therefore, the clustered DNA damage with high complexity still needs to be considered in the study of radiation biological effects, in spite of their small contributions to all clustered DNA damage.

Author Correction: Differential electron emission from polycyclic aromatic hydrocarbon molecules under fast ion impact.

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

Comparison of gadolinium nanoparticles and molecular contrast agents for radiation therapy-enhancement.

PURPOSE: Nanoparticles appear as a novel tool to enhance the effectiveness of radiotherapy in cancer treatments. Many parameters influence their efficacy, such as their size, concentration, composition, their cellular localization, as well as the photon source energy. The current Monte Carlo study aims at comparing the dose-enhancement in presence of gadolinium (Gd), either as isolated atoms or atoms clustered in nanoparticles (NPs), by investigating the role played by these physical parameters at the cellular and the nanometer scale. In parallel, in vitro assays were performed in presence of either the gadolinium contrast agent (GdCA) Magnevist® or ultrasmall gadolinium NPs (GdNPs, 3 nm) for comparison with the simulations. METHODS: PENELOPE Monte Carlo Code was used for in silico dose calculations. Monochromatic photon beams were used to calculate dose enhancements in different cell compartments and low-energy secondary electron spectra dependence with energy. Particular attention has been placed on the interplay between the X-ray beam energy, the Gd localization and its distance from cellular targets. Clonogenic assays were used to quantify F98 rat glioma cell survival after irradiation in the presence of GdNPs or GdCA, using monochromatic X-rays with energies in the 30 keV-80 keV range from a synchrotron and 1.25 MeV gamma photons from a cobalt-60 source. The simulations that correspond to the experimental conditions were compared with the experimental results. RESULTS: In silico, a highly heterogeneous and clustered Gd-atom distribution, a massive production of low energy electrons around GdNPs and an optimal X-ray beam energy, above the Gd K-edge, were key factors found to increase microscopic doses, which could potentially induce cell death. The different Gd localizations studied all resulted in a lower dose enhancement for the nucleus component than for cytoplasm or membrane compartments, with a maximum dose-enhancement factor (DEF) found at 65 keV and 58 keV, respectively. In vitro, radiosensitization was observed with GdNPs incubated 5 h with the cells (2.1 mg Gd/mL) at all energies. Experimental DEFs were found to be greater than computational DEFs but follow a similar trend with irradiation energy. However, an important radiosensitivity was observed experimentally with GdNPs at high energy (1.25 MeV), whereas no effect was expected from modeling. This effect was correlated with GdNPs incubation time. In vitro, GdCA provided no dose enhancement at 1.25 MeV energies, in agreement with computed data. CONCLUSIONS: These results provide a foundation on which to base optimizations of the physical parameters in Gd radiation-enhanced therapy. Strong evidence was provided that GdCA or GdNPs could both be used for radiation dose-enhancement therapy. There in vivo biological distribution, in the tumor volume and at the cellular scale, will be the key factor for providing large dose enhancements and determine their therapeutic efficacy.

Differential electron emission from polycyclic aromatic hydrocarbon molecules under fast ion impact.

Interaction between polycyclic aromatic hydrocarbon (PAH) molecule and energetic ion is a subject of interest in different areas of modern physics. Here, we present measurements of energy and angular distributions of absolute double differential electron emission cross section for coronene (C24H12) and fluorene (C13H10) molecules under fast bare oxygen ion impact. For coronene, the angular distributions of the low energy electrons are quite different from that of simpler targets like Ne or CH4, which is not the case for fluorene. The behaviour of the higher electron energy distributions for both the targets are similar to that for simple targets. In case of coronene, a clear signature of plasmon resonance is observed in the analysis of forward-backward angular asymmetry of low energy electron emission. For fluorene, such signature is not identified probably due to lower oscillator strength of plasmon compared to the coronene. The theoretical calculation based on the first-order Born approximation with correct boundary conditions (CB1), in general, reproduced the experimental observations qualitatively, for both the molecules, except in the low energy region for coronene, which again indicates the role of collective excitation. Single differential and total cross sections are also deduced. An overall comparative study is presented.

Calculation on spectrum of direct DNA damage induced by low-energy electrons including dissociative electron attachment.

In this work, direct DNA damage induced by low-energy electrons (sub-keV) is simulated using a Monte Carlo method. The characteristics of the present simulation are to consider the new mechanism of DNA damage due to dissociative electron attachment (DEA) and to allow determining damage to specific bases (i.e., adenine, thymine, guanine, or cytosine). The electron track structure in liquid water is generated, based on the dielectric response model for describing electron inelastic scattering and on a free-parameter theoretical model and the NIST database for calculating electron elastic scattering. Ionization cross sections of DNA bases are used to generate base radicals, and available DEA cross sections of DNA components are applied for determining DNA-strand breaks and base damage induced by sub-ionization electrons. The electron elastic scattering from DNA components is simulated using cross sections from different theoretical calculations. The resulting yields of various strand breaks and base damage in cellular environment are given. Especially, the contributions of sub-ionization electrons to various strand breaks and base damage are quantitatively presented, and the correlation between complex clustered DNA damage and the corresponding damaged bases is explored. This work shows that the contribution of sub-ionization electrons to strand breaks is substantial, up to about 40-70%, and this contribution is mainly focused on single-strand break. In addition, the base damage induced by sub-ionization electrons contributes to about 20-40% of the total base damage, and there is an evident correlation between single-strand break and damaged base pair A-T.

Single- and Double-Strand Breaks of Dry DNA Exposed to Protons at Bragg-Peak Energies.

Ultrathin layers (<20 nm) of pBR322 plasmid DNA were deposited onto 2.5 µm thick polyester films and exposed to proton Bragg-peak energies (90-3000 keV) at various fluences. A quantitative analysis of radio-induced DNA damage is reported here in terms of single- and double-strand breaks (SSB and DSB, respectively). The corresponding yields as well as G-values and the cross sections exhibit fairly good agreement with the rare available data, stemming from close experimental conditions, namely, based on α particle irradiation. SSB/DSB rates appear to be linear when plotted against linear energy transfer (LET) in the whole energy range studied. All the data present a maximum in the 150-200 keV energy range; as for LET, it peaks at 90 keV. We also show that fragmentation starts to be significant for proton fluences greater than 1 × 1011 cm-2 at the Bragg-peak energies. Finally, we determine the average proton track radial extension, rmax, corresponding to an occupation probability of 100% DSB in the Bragg-peak region. The rmax values determined are in excellent agreement with the radial extensions of proton tracks determined by simulation approaches in water. When plotted as a function of LET, both SSB and DSB cross sections bend back at high LETs.

Double differential cross sections for proton induced electron emission from molecular analogues of DNA constituents for energies in the Bragg peak region.

For track structure simulations in the Bragg peak region, measured electron emission cross sections of DNA constituents are required as input for developing parameterized model functions representing the scattering probabilities. In the present work, double differential cross sections were measured for the electron emission from vapor-phase pyrimidine, tetrahydrofuran, and trimethyl phosphate that are structural analogues to the base, the sugar, and the phosphate residue of the DNA, respectively. The range of proton energies was from 75 keV to 135 keV, the angles ranged from 15° to 135°, and the electron energies were measured from 10 eV to 200 eV. Single differential and total electron emission cross sections are derived by integration over angle and electron energy and compared to the semi-empirical Hansen-Kocbach-Stolterfoht (HKS) model and a quantum mechanical calculation employing the first Born approximation with corrected boundary conditions (CB1). The CB1 provides the best prediction of double and single differential cross section, while total cross sections can be fitted with semi-empirical models. The cross sections of the three samples are proportional to their total number of valence electrons.

Comparison between Three Promising ß-emitting Radionuclides, (67)Cu, (47)Sc and (161)Tb, with Emphasis on Doses Delivered to Minimal Residual Disease.

PURPOSE: Radionuclide therapy is increasingly seen as a promising option to target minimal residual disease. Copper-67, scandium-47 and terbium-161 have a medium-energy ß(-) emission which is similar to that of lutetium-177, but offer the advantage of having diagnostic partner isotopes suitable for pretreatment imaging. The aim of this study was to compare the efficacy of (67)Cu, (47)Sc and (161)Tb to irradiate small tumors. METHODS: The absorbed dose deriving from a homogeneous distribution of (67)Cu, (47)Sc or (161)Tb in water-density spheres was calculated with the Monte Carlo code CELLDOSE. The diameters of the spheres ranged from 5 mm to 10 µm, thus simulating micrometastases or single tumor cells. All electron emissions, including ß(-) spectra, Auger and conversion electrons were taken into account. Because these radionuclides differ in electron energy per decay, the simulations were run assuming that 1 MeV was released per µm(3), which would result in a dose of 160 Gy if totally absorbed. RESULTS: The absorbed dose was similar for the three radionuclides in the 5-mm sphere (146-149 Gy), but decreased differently in smaller spheres. In particular, (161)Tb delivered higher doses compared to the other radionuclides. For instance, in the 100-µm sphere, the absorbed dose was 24.1 Gy with (67)Cu, 14.8 Gy with (47)Sc and 44.5 Gy with (161)Tb. Auger and conversion electrons accounted for 71% of (161)Tb dose. The largest dose differences were found in cell-sized spheres. In the 10-µm sphere, the dose delivered by (161)Tb was 4.1 times higher than that from (67)Cu and 8.1 times that from (47)Sc. CONCLUSION: (161)Tb can effectively irradiate small tumors thanks to its decay spectrum that combines medium-energy ß(-) emission and low-energy conversion and Auger electrons. Therefore (161)Tb might be a better candidate than (67)Cu and (47)Sc for treating minimal residual disease in a clinical setting.

Experimental and theoretical double differential cross sections for electron impact ionization of methane.

Experimental and theoretical double differential cross sections (DDCSs) for electron-induced ionization of methane (CH4) are here reported for primary energies ranging from 50 eV to 350 eV and ejection angles between 25° and 130°. Experimental DDCSs are compared with theoretical predictions performed within the first Born approximation Coulomb wave. In this model, the initial molecular state is described by using single center wave functions, the incident (scattered) electron being described by a plane wave, while a Coulomb wave function is used for modeling the secondary ejected electron. A fairly good agreement may be observed between theory and experiment with nevertheless an expected systematic overestimation of the theory at low-ejection energies (<50 eV).

Dose Deposits from 90Y, 177Lu, 111In, and 161Tb in Micrometastases of Various Sizes: Implications for Radiopharmaceutical Therapy.

UNLABELLED: Radiopharmaceutical therapy, traditionally limited to refractory metastatic cancer, is being increasingly used at earlier stages, such as for treating minimal residual disease. The aim of this study was to compare the effectiveness of (90)Y, (177)Lu, (111)In, and (161)Tb at irradiating micrometastases. (90)Y and (177)Lu are widely used ß(-)-emitting radionuclides. (161)Tb is a medium-energy ß(-) radionuclide that is similar to (177)Lu but emits a higher percentage of conversion and Auger electrons. (111)In emits γ-photons and conversion and Auger electrons. METHODS: We used the Monte Carlo code CELLDOSE to assess electron doses from a uniform distribution of (90)Y, (177)Lu, (111)In, or (161)Tb in spheres with diameters ranging from 10 mm to 10 µm. Because these isotopes differ in electron energy per decay, the doses were compared assuming that 1 MeV was released per µm(3), which would result in 160 Gy if totally absorbed. RESULTS: In a 10-mm sphere, the doses delivered by (90)Y, (177)Lu, (111)In, and (161)Tb were 96.5, 152, 153, and 152 Gy, respectively. The doses decreased along with the decrease in sphere size, and more abruptly so for (90)Y. In a 100-µm metastasis, the dose delivered by (90)Y was only 1.36 Gy, compared with 24.5 Gy for (177)Lu, 38.9 Gy for (111)In, and 44.5 Gy for (161)Tb. In cell-sized spheres, the dose delivered by (111)In and (161)Tb was higher than that of (177)Lu. For instance, in a 10-µm cell, (177)Lu delivered 3.92 Gy, compared with 22.8 Gy for (111)In and 14.1 Gy for (161)Tb. CONCLUSION: (177)Lu, (111)In, and (161)Tb might be more appropriate than (90)Y for treating minimal residual disease. (161)Tb is a promising radionuclide because it combines the advantages of a medium-energy ß(-) emission with those of Auger electrons and emits fewer photons than (111)In.

Quantum-mechanical predictions of electron-induced ionization cross sections of DNA components.

Ionization of biomolecules remains still today rarely investigated on both the experimental and the theoretical sides. In this context, the present work appears as one of the first quantum mechanical approaches providing a multi-differential description of the electron-induced ionization process of the main DNA components for impact energies ranging from the target ionization threshold up to about 10 keV. The cross section calculations are here performed within the 1st Born approximation framework in which the ejected electron is described by a Coulomb wave whereas the incident and the scattered electrons are both described by a plane wave. The biological targets of interest, namely, the DNA nucleobases and the sugar-phosphate backbone, are here described by means of the GAUSSIAN 09 system using the restricted Hartree-Fock method with geometry optimization. The theoretical predictions also obtained have shown a reasonable agreement with the experimental total ionization cross sections while huge discrepancies have been pointed out with existing theoretical models, mainly developed within a semi-classical framework.