Cellular lethal damage of 64Cu incorporated in mammalian genome evaluated with Monte Carlo methods

PurposeTargeted Radionuclide Therapy (TRT) with Auger Emitters (AE) is a technique that allows targeting specific sites on tumor cells using radionuclides. The toxicity of AE is critically dependent on its proximity to the DNA. The aim of this study is to quantify the DNA damage and radiotherapeutic...

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Main Authors: Jhonatan Carrasco-Hernandez, José Ramos-Méndez, Elizabeth Padilla-Rodal, Miguel A. Avila-Rodriguez
Format: Article
Language:English
Published: Frontiers Media S.A. 2023-09-01
Series:Frontiers in Medicine
Subjects:
Online Access:https://www.frontiersin.org/articles/10.3389/fmed.2023.1253746/full
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author Jhonatan Carrasco-Hernandez
José Ramos-Méndez
Elizabeth Padilla-Rodal
Miguel A. Avila-Rodriguez
author_facet Jhonatan Carrasco-Hernandez
José Ramos-Méndez
Elizabeth Padilla-Rodal
Miguel A. Avila-Rodriguez
author_sort Jhonatan Carrasco-Hernandez
collection DOAJ
description PurposeTargeted Radionuclide Therapy (TRT) with Auger Emitters (AE) is a technique that allows targeting specific sites on tumor cells using radionuclides. The toxicity of AE is critically dependent on its proximity to the DNA. The aim of this study is to quantify the DNA damage and radiotherapeutic potential of the promising AE radionuclide copper-64 (64Cu) incorporated into the DNA of mammalian cells using Monte Carlo track-structure simulations.MethodsA mammalian cell nucleus model with a diameter of 9.3 μm available in TOPAS-nBio was used. The cellular nucleus consisted of double-helix DNA geometrical model of 2.3 nm diameter surrounded by a hydration shell with a thickness of 0.16 nm, organized in 46 chromosomes giving a total of 6.08 giga base-pairs (DNA density of 14.4 Mbp/μm3). The cellular nucleus was irradiated with monoenergetic electrons and radiation emissions from several radionuclides including 111In, 125I, 123I, and 99mTc in addition to 64Cu. For monoenergetic electrons, isotropic point sources randomly distributed within the nucleus were modeled. The radionuclides were incorporated in randomly chosen DNA base pairs at two positions near to the central axis of the double-helix DNA model at (1) 0.25 nm off the central axis and (2) at the periphery of the DNA (1.15 nm off the central axis). For all the radionuclides except for 99mTc, the complete physical decay process was explicitly simulated. For 99mTc only total electron spectrum from published data was used. The DNA Double Strand Breaks (DSB) yield per decay from direct and indirect actions were quantified. Results obtained for monoenergetic electrons and radionuclides 111In, 125I, 123I, and 99mTc were compared with measured and calculated data from the literature for verification purposes. The DSB yields per decay incorporated in DNA for 64Cu are first reported in this work. The therapeutic effect of 64Cu (activity that led 37% cell survival after two cell divisions) was determined in terms of the number of atoms incorporated into the nucleus that would lead to the same DSBs that 100 decays of 125I. Simulations were run until a 2% statistical uncertainty (1 standard deviation) was achieved.ResultsThe behavior of DSBs as a function of the energy for monoenergetic electrons was consistent with published data, the DSBs increased with the energy until it reached a maximum value near 500 eV followed by a continuous decrement. For 64Cu, when incorporated in the genome at evaluated positions (1) and (2), the DSB were 0.171 ± 0.003 and 0.190 ± 0.003 DSB/decay, respectively. The number of initial atoms incorporated into the genome (per cell) for 64Cu that would cause a therapeutic effect was estimated as 3,107 ± 28, that corresponds to an initial activity of 47.1 ± 0.4 × 10−3 Bq.ConclusionOur results showed that TRT with 64Cu has comparable therapeutic effects in cells as that of TRT with radionuclides currently used in clinical practice.
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spelling doaj.art-1e70d9bb68844643b34b7c333dcd2c4a2023-09-29T09:22:58ZengFrontiers Media S.A.Frontiers in Medicine2296-858X2023-09-011010.3389/fmed.2023.12537461253746Cellular lethal damage of 64Cu incorporated in mammalian genome evaluated with Monte Carlo methodsJhonatan Carrasco-Hernandez0José Ramos-Méndez1Elizabeth Padilla-Rodal2Miguel A. Avila-Rodriguez3Departamento de Estructura de la Materia, Instituto de Ciencias Nucleares, Universidad Nacional Autónoma de México, Mexico City, MexicoDepartment of Radiation Oncology, University of California, San Francisco, San Francisco, CA, United StatesDepartamento de Estructura de la Materia, Instituto de Ciencias Nucleares, Universidad Nacional Autónoma de México, Mexico City, MexicoUnidad Radiofarmacia-Ciclotrón, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, MexicoPurposeTargeted Radionuclide Therapy (TRT) with Auger Emitters (AE) is a technique that allows targeting specific sites on tumor cells using radionuclides. The toxicity of AE is critically dependent on its proximity to the DNA. The aim of this study is to quantify the DNA damage and radiotherapeutic potential of the promising AE radionuclide copper-64 (64Cu) incorporated into the DNA of mammalian cells using Monte Carlo track-structure simulations.MethodsA mammalian cell nucleus model with a diameter of 9.3 μm available in TOPAS-nBio was used. The cellular nucleus consisted of double-helix DNA geometrical model of 2.3 nm diameter surrounded by a hydration shell with a thickness of 0.16 nm, organized in 46 chromosomes giving a total of 6.08 giga base-pairs (DNA density of 14.4 Mbp/μm3). The cellular nucleus was irradiated with monoenergetic electrons and radiation emissions from several radionuclides including 111In, 125I, 123I, and 99mTc in addition to 64Cu. For monoenergetic electrons, isotropic point sources randomly distributed within the nucleus were modeled. The radionuclides were incorporated in randomly chosen DNA base pairs at two positions near to the central axis of the double-helix DNA model at (1) 0.25 nm off the central axis and (2) at the periphery of the DNA (1.15 nm off the central axis). For all the radionuclides except for 99mTc, the complete physical decay process was explicitly simulated. For 99mTc only total electron spectrum from published data was used. The DNA Double Strand Breaks (DSB) yield per decay from direct and indirect actions were quantified. Results obtained for monoenergetic electrons and radionuclides 111In, 125I, 123I, and 99mTc were compared with measured and calculated data from the literature for verification purposes. The DSB yields per decay incorporated in DNA for 64Cu are first reported in this work. The therapeutic effect of 64Cu (activity that led 37% cell survival after two cell divisions) was determined in terms of the number of atoms incorporated into the nucleus that would lead to the same DSBs that 100 decays of 125I. Simulations were run until a 2% statistical uncertainty (1 standard deviation) was achieved.ResultsThe behavior of DSBs as a function of the energy for monoenergetic electrons was consistent with published data, the DSBs increased with the energy until it reached a maximum value near 500 eV followed by a continuous decrement. For 64Cu, when incorporated in the genome at evaluated positions (1) and (2), the DSB were 0.171 ± 0.003 and 0.190 ± 0.003 DSB/decay, respectively. The number of initial atoms incorporated into the genome (per cell) for 64Cu that would cause a therapeutic effect was estimated as 3,107 ± 28, that corresponds to an initial activity of 47.1 ± 0.4 × 10−3 Bq.ConclusionOur results showed that TRT with 64Cu has comparable therapeutic effects in cells as that of TRT with radionuclides currently used in clinical practice.https://www.frontiersin.org/articles/10.3389/fmed.2023.1253746/fulltargeted radionuclide therapyAuger emittersDNATOPAS-nBiocopper-64
spellingShingle Jhonatan Carrasco-Hernandez
José Ramos-Méndez
Elizabeth Padilla-Rodal
Miguel A. Avila-Rodriguez
Cellular lethal damage of 64Cu incorporated in mammalian genome evaluated with Monte Carlo methods
Frontiers in Medicine
targeted radionuclide therapy
Auger emitters
DNA
TOPAS-nBio
copper-64
title Cellular lethal damage of 64Cu incorporated in mammalian genome evaluated with Monte Carlo methods
title_full Cellular lethal damage of 64Cu incorporated in mammalian genome evaluated with Monte Carlo methods
title_fullStr Cellular lethal damage of 64Cu incorporated in mammalian genome evaluated with Monte Carlo methods
title_full_unstemmed Cellular lethal damage of 64Cu incorporated in mammalian genome evaluated with Monte Carlo methods
title_short Cellular lethal damage of 64Cu incorporated in mammalian genome evaluated with Monte Carlo methods
title_sort cellular lethal damage of 64cu incorporated in mammalian genome evaluated with monte carlo methods
topic targeted radionuclide therapy
Auger emitters
DNA
TOPAS-nBio
copper-64
url https://www.frontiersin.org/articles/10.3389/fmed.2023.1253746/full
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