The effect of <sup>111</sup>In radionuclide distance and auger electron energy on direct induction of DNA double-strand breaks: a Monte Carlo study using Geant4 toolkit

Piroozfar, Behnaz; Raisali, Gholamreza; Alirezapour, Behrouz; Mirzaii, M.

doi:10.1080/09553002.2018.1440329

Cited by 11 publications

(10 citation statements)

References 47 publications

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“…In silico simulation studies have also been reported, demonstrating that the number of DSBs induced by Auger electron-emitters and other MRT radionuclides depends on their proximity to the DNA as well as the DNA form, e.g. B-form [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

Validation of the plasmid study to relate DNA damaging effects of radionuclides to those from external beam radiotherapy

Verger

Cheng

Santis

et al. 2021

Nuclear Medicine and Biology

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Introduction The biological consequences of absorbed radiation doses are ill-defined for radiopharmaceuticals, unlike for external beam radiotherapy (EBRT). A reliable assay that assesses the biological consequences of any radionuclide is much needed. Here, we evaluated the cell-free plasmid DNA assay to determine the relative biological effects of radionuclides such as Auger electron-emitting [ 67 Ga]GaCl 3 or [ 111 In]InCl 3 compared to EBRT. Methods Supercoiled pBR322 plasmid DNA (1.25 or 5 ng/μL) was incubated with 0.5 or 1 MBq [ 67 Ga]GaCl 3 or [ 111 In]InCl 3 for up to 73 h or was exposed to EBRT( 137 Cs; 5 Gy/min; 0-40 Gy). The induction of relaxed and linear plasmid DNA, representing single and double strand breaks, respectively, was assessed by gel electrophoresis. Chelated forms of 67 Ga were also investigated using DOTA and THP. Topological conversion rates for supercoiled-to-relaxed or relaxed-to-linear DNA were obtained by fitting a kinetic model. Results DNA damage increased both with EBRT dose and incubation time for [ 67 Ga]GaCl 3 and [ 111 In]InCl 3 . Damage caused by [ 67 Ga]GaCl 3 decreased when chelated. [ 67 Ga]GaCl 3 proved more damaging than [ 111 In]InCl 3 ; 1.25 ng/μL DNA incubated with 0.5 MBq [ 67 Ga]GaCl 3 for 2 h led to a 70% decrease of intact plasmid DNA as opposed to only a 19% decrease for [ 111 In]InCl 3 . For both EBRT and radionuclides, conversion rates were slower for 5 ng/μL than 1.25 ng/μL plasmid DNA. DNA damage caused by 1 Gy EBRT was the equivalent to damage caused by 0.5 MBq unchelated [ 67 Ga]GaCl 3 and [ 111 In]InCl 3 after 2.05 ± 0.36 and 9.3 ± 0.77 h of incubation, respectively. Conclusions This work has highlighted the power of the plasmid DNA assay for a rapid determination of the relative biological effects of radionuclides compared to external beam radiotherapy. It is envisaged this approach will enable the systematic assessment of imaging and therapeutic radionuclides, including Auger electron-emitters, to further inform radiopharmaceutical design and application.

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Section: Discussionmentioning

confidence: 99%

Validation of the plasmid study to relate DNA damaging effects of radionuclides to those from external beam radiotherapy

Verger

Cheng

Santis

et al. 2021

Nuclear Medicine and Biology

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“…111 In emits per decay 14.7 AE of broad energy and range spectrum varying from 0.0085 keV (0.251 nm) to 22.5 keV (13600 nm) ( Howell, 1992 ). The dependence of direct induction of DNA double-strand breaks by AE emitted by 111 In on their energy and distance from the DNA center has been simulated recently ( Piroozfar et al, 2018 ). With both the emission probability and efficiency of electron energy taken into consideration, 350 eV AE produced the maximum number of double-strand breaks.…”

Section: Discussionmentioning

confidence: 99%

“…With both the emission probability and efficiency of electron energy taken into consideration, 350 eV AE produced the maximum number of double-strand breaks. Though the range of 350 eV AE in water is estimated to be 16.4 nm ( Howell, 1992 ), simulation data determined a 6-nm distance of decaying 111 In from the DNA center as a cutoff for substantial contribution to double-strand breaks formation ( Piroozfar et al, 2018 ). Assuming homogenous distribution of nuclear DNA [3 × 10 9 base pairs ( Ratilainen et al, 2001 ) resulting in approximately 2 m length of human diploid nuclear DNA in a cell], we can estimate the mean distance from any point inside the nucleus to the DNA central axis, ranging from 5.3 nm to 13.5 nm for cell nuclei diameter of 7 to 13 μm, respectively.…”

Section: Discussionmentioning

confidence: 99%

Antitumor Activity of Auger Electron Emitter 111In Delivered by Modular Nanotransporter for Treatment of Bladder Cancer With EGFR Overexpression

et al. 2018

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Gamma-ray emitting 111In, which is extensively used for imaging, is also a source of short-range Auger electrons (AE). While exhibiting negligible effect outside cells, these AE become highly toxic near DNA within the cell nucleus. Therefore, these radionuclides can be used as a therapeutic anticancer agent if delivered precisely into the nuclei of tumor target cells. Modular nanotransporters (MNTs) designed to provide receptor-targeted delivery of short-range therapeutic cargoes into the nuclei of target cells are perspective candidates for specific intracellular delivery of AE emitters. The objective of this study was to evaluate the in vitro and in vivo efficacy of 111In attached MNTs to kill human bladder cancer cells overexpressing epidermal growth factor receptor (EGFR). The cytotoxicity of 111In delivered by the EGFR-targeted MNT (111In-MNT) was greatly enhanced on EJ-, HT-1376-, and 5637-expressing EGFR bladder cancer cell lines compared with 111In non-targeted control. In vivo microSPECT/CT imaging and antitumor efficacy studies revealed prolonged intratumoral retention of 111In-MNT with t½ = 4.1 ± 0.5 days as well as significant dose-dependent tumor growth delay (up to 90% growth inhibition) after local infusion of 111In-MNT in EJ xenograft-bearing mice.

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“…3) and photons (X-rays and γ-rays) were extracted from the publication of the American Association of Physicists in Medicine 39 (AAPM), as it is still a reference for Auger electron emitters (e.g., Refs. [14,40,41]). Table I shows important properties of the decay of 125 I and 111 In.…”

Section: C2 Auger Electron Emittersmentioning

confidence: 99%

Monte Carlo dosimetry of a realistic multicellular model of follicular lymphoma in a context of radioimmunotherapy

et al. 2020

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Small-scale dosimetry studies generally consider an artificial environment where the tumors are spherical and the radionuclides are homogeneously biodistributed. However, tumor shapes are irregular and radiopharmaceutical biodistributions are heterogeneous, impacting the energy deposition in targeted radionuclide therapy. To bring realism, we developed a dosimetric methodology based on a three-dimensional in vitro model of follicular lymphoma incubated with rituximab, an anti-CD20 monoclonal antibody used in the treatment of non-Hodgkin lymphomas, which might be combined with a radionuclide. The effects of the realistic geometry and biodistribution on the absorbed dose were highlighted by comparison with literature data. Additionally, to illustrate the possibilities of this methodology, the effect of different radionuclides on the absorbed dose distribution delivered to the in vitro tumor were compared. Methods: The starting point was a model named multicellular aggregates of lymphoma cells (MALC). Three MALCs of different dimensions and their rituximab biodistribution were considered. Geometry, antibody location and concentration were extracted from selective plane illumination microscopy. Assuming antibody radiolabeling with Auger electron (125 I and 111 In) and β − particle emitters (177 Lu, 131 I and 90 Y), we simulated energy deposition in MALCs using two Monte Carlo codes: Geant4-DNA with "CPA100" physics models for Auger electron emitters and Geant4 with "Livermore" physics models for β − particle emitters. Results: MALCs had ellipsoid-like shapes with major radii, r, of~0.25,~0.5 and~1.3 mm. Rituximab was concentrated in the periphery of the MALCs. The absorbed doses delivered by 177 Lu, 131 I and 90 Y in MALCs were compared with literature data for spheres with two types of homogeneous biodistributions (on the surface or throughout the volume). Compared to the MALCs, the mean absorbed doses delivered in spheres with surface biodistributions were between 18% and 38% lower, while with volume biodistribution they were between 15% and 29% higher. Regarding the radionuclides comparison, the relationship between MALC dimensions, rituximab biodistribution and

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The effect of ¹¹¹In radionuclide distance and auger electron energy on direct induction of DNA double-strand breaks: a Monte Carlo study using Geant4 toolkit

Abstract: The results show that the most effective Auger electrons are the 350 eV electrons from In atoms with<4 nm distance from the central axis of the DNA which induce ∼1.3 DSBs per decay when bound to the DNA. This value seems reasonable when compared with the reported experimental data.

Cited by 11 publications

References 47 publications

Validation of the plasmid study to relate DNA damaging effects of radionuclides to those from external beam radiotherapy

Validation of the plasmid study to relate DNA damaging effects of radionuclides to those from external beam radiotherapy

Antitumor Activity of Auger Electron Emitter 111In Delivered by Modular Nanotransporter for Treatment of Bladder Cancer With EGFR Overexpression

Monte Carlo dosimetry of a realistic multicellular model of follicular lymphoma in a context of radioimmunotherapy

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The effect of 111In radionuclide distance and auger electron energy on direct induction of DNA double-strand breaks: a Monte Carlo study using Geant4 toolkit

Abstract: The results show that the most effective Auger electrons are the 350 eV electrons from In atoms with<4 nm distance from the central axis of the DNA which induce ∼1.3 DSBs per decay when bound to the DNA. This value seems reasonable when compared with the reported experimental data.

Cited by 11 publications

References 47 publications

Validation of the plasmid study to relate DNA damaging effects of radionuclides to those from external beam radiotherapy

Validation of the plasmid study to relate DNA damaging effects of radionuclides to those from external beam radiotherapy

Antitumor Activity of Auger Electron Emitter 111In Delivered by Modular Nanotransporter for Treatment of Bladder Cancer With EGFR Overexpression

Monte Carlo dosimetry of a realistic multicellular model of follicular lymphoma in a context of radioimmunotherapy

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The effect of ¹¹¹In radionuclide distance and auger electron energy on direct induction of DNA double-strand breaks: a Monte Carlo study using Geant4 toolkit