Iranian Journal of Medical Physics

Iranian Journal of Medical Physics

Investigation of Alternative Metals for Gold Nanoparticles in Enhancing Proton Therapy Relative Biological Effectiveness: A Monte Carlo Study

Document Type : Original Paper

Authors
Fatemeh Habibi 1
Zohreh Parang 1
Nasrin Hoseini-Motlagh 1
Alireza Keshavarz 2
1 Department of Physics, Shi.C., Islamic Azad University, Shiraz, Iran
2 Shiraz University of Technology
10.22038/ijmp.2026.94381.2676
Abstract
Introduction: This study investigates the enhancement of relative biological effectiveness (RBE) in proton therapy for ocular tumors using heavy metal nanoparticles using Monte Carlo simulation.
Material and Methods: Through multiscale Monte Carlo simulations with Geant4-DNA, we evaluated the impact of gold (Au), bismuth (Bi), iridium (Ir), and platinum (Pt) nanoparticles (with 25 nm radius and 30 mg/g concentration) on the RBE of a 62-MeV spread-out Bragg peak (SOBP). A mammalian fibroblast cell nucleus was simulated and DNA damages induced by protons (with and without the presence of nanoparticles) were calculated as biological endpoint for RBE calculation.
Results: The results demonstrated that all nanoparticles increased RBE compared to the nanoparticle-free condition. Pt and Ir nanoparticles yielded the greatest enhancement, outperforming Au, while Bi nanoparticles provided the least improvement. The most substantial RBE increase occurred at the distal end of the SOBP, correlating with the region of highest linear energy transfer (LET). Calculations based on DNA damage and cell survival curves confirmed that the choice of biological endpoint significantly influences the computed RBE values. A key finding was that nanoparticle density, rather than atomic number, was the dominant factor in RBE improvement. This suggests that high-density Pt nanoparticles are a more effective radio-sensitizer than Au.
Conclusion: The study underscores the importance of incorporating variable RBE models and radiobiological effects of nanoparticles into proton therapy treatment planning systems to improve clinical outcomes.
Keywords
Proton Therapy RBE Nanoparticle Monte Carlo Simulation Geant4
DNA
Subjects
1.        Jager MJ, Shields CL, Cebulla CM, Abdel-Rahman MH, Grossniklaus HE, Stern MH, et al. Uveal melanoma. Nat Rev Dis Primers. 2020 Apr 9;6(1):24.
2.        Mohan R. A review of proton therapy – current status and future directions. Precis Radiat Oncol. 2022 Mar;6(2):164-176.
3.        Polf JC, Bronk LF, Driessen WH, Arap W, Pasqualini R, Gillin M. Enhanced relative biological effectiveness of proton radiotherapy in tumor cells with internalized gold nanoparticles. Appl Phys Lett. 2011 May 11;98(19):193702.
4.        Hojo H, Dohmae T, Hotta K, Kohno R, Motegi A, Yagishita A, et al. Difference in the relative biological effectiveness and DNA damage repair processes in response to proton beam therapy according to the positions of the spread-out Bragg peak. Radiat Oncol. 2017 Jun 22;12(1):111.
5.        Torrisi L, Davidkova M, Havranek V, Cutroneo M, and Torrisi A. Physical study of proton therapy at CANAM laboratory on medulloblastoma cell lines DAOY. Radiat Eff Defects Solids. 2020 Oct;175(9-10):863-878.
6.        Habibi F, Parang Z, Keshavarz A. Hadron therapy with nanoparticles for dose enhancement and estimation of DNA damage using GEANT4. Jordan J Phys. 2025 Dec 31;18(5):643-58.
7.        Habibi F, Parang Z, Hoseini-Motlagh N, Keshavarz A. Proton therapy enhancement with gold, platinum, and iridium nanoparticle: A cellular-scale Geant4-DNA study. Radiat Phys Eng. 2026;7(3):1-14.
8.        Archer JW, Large MJ, Bolst D, Sakata D, Tran HN, Chatzipapas KP, et al. A multiscale nanodosimetric study of GCR protons and alpha particles in the organs of astronauts on the lunar surface. Radiat Phys Chem. 2025; 229: 112448.
9.        Vafapour H, Rafiepour P, Moradgholi J, Mortazavi SMJ. Evaluating the biological impact of shelters on astronaut health during different solar particle events: A Geant4-DNA simulation study. Radiat Environ Biophys. 2025 Jan;64(1):137-150.
10.     Paganetti H, Niemierko A, Ancukiewicz M, Gerweck LE, Goitein M, Loeffler JS, Suit HD. Relative biological effectiveness (RBE) values for proton beam therapy. Int J Radiat Oncol Biol Phys. 2002 Jun;53(2):407-421.
11.     Paganetti H. Relative biological effectiveness (RBE) values for proton beam therapy: Variations as a function of biological endpoint, dose, and linear energy transfer. Phys Med Biol. 2014 Nov;59(22).
12.     McMahon SJ. Proton RBE models: commonalities and differences. Phys Med Biol. 2021 Feb;66(4):04NT02.
13.     Incerti S, Baldacchino G, Bernal M, Capra R, Champion C, Francis Z, et al. The Geant4-DNA project. Int J Model Simul Sci Comput. 2010 Jun;1(2):157-178.
14.     Schuemann J, McNamara AL, Ramos-Méndez J, Perl J, Held KD, et al. TOPAS-nBio: An extension to the TOPAS simulation toolkit for cellular and sub-cellular radiobiology. Radiat Res. 2019 Feb;191(2):125-138.
15.     Kyriakou I, Sakata D, Tran HN, Perrot Y, Shin WG, Lampe N, et al. Review of the Geant4-DNA simulation toolkit for radiobiological applications at the cellular and DNA level. Cancers. 2021 Dec;14(1):35.
16.     Nikjoo H, Taleei R, Liamsuwan T, Liljequist D, Emfietzoglou D. Perspectives in radiation biophysics: From radiation track structure simulation to mechanistic models of DNA damage and repair. Radiat Phys Chem. 2016 Nov;128:3-10.
17.     Martínez-Rovira I, Prezado Y. Evaluation of the local dose enhancement in the combination of proton therapy and nanoparticles. Med Phys. 2015 Nov;42(11):6703-6710.
18.     Peukert D, Kempson I, Douglass M, Bezak E. Gold nanoparticle enhanced proton therapy: A Monte Carlo simulation of the effects of proton energy, nanoparticle size, coating material, and coating thickness on dose and radiolysis yield. Med Phys. 2020 Feb;47(2):651-661.
19.     Taheri A, Khandaker MU, Moradi F, Bradley DA. A review of recent advances in the modeling of nanoparticle radiosensitization with the Geant4-DNA toolkit. Radiat Phys Chem. 2023;207:111146.
20.     Mansouri E, Almisned G, Tekin HO, Rajabpour S, Mesbahi A. Radiosensitization with metallic nanoparticles under MeV proton beams: local dose enhancement. Radiat Environ Biophys. 2024 Dec;63(4):537-543.
21.     Agostinelli S, Allison J, Amako KA, Apostolakis J, Araujo H, Arce P, et al. Geant4—a simulation toolkit. Nucl Instrum Methods Phys Res A. 2003 Jul;506(3):250-303.
22.     Allison J, Amako K, Apostolakis J, Arce P, Asai M, Aso T, et al. Recent developments in Geant4. Nucl Instrum Methods Phys Res A. 2016 Dec;835:186-225.
23.     Kyriakou I, Incerti S, Francis Z. Technical note: Improvements in Geant4 energy-loss model and the effect on low-energy electron transport in liquid water. Med Phys. 2015 Jul;42(7):3870-3876.
24.     Ramos‐Méndez J, Shin WG, Karamitros M, Domínguez‐Kondo J, Tran NH, Incerti S, et al. Independent reaction times method in Geant4-DNA: Implementation and performance. Med Phys. 2020 Nov;47(11):5919-5930.
25.     Chatzipapas KP, Tran NH, Dordevic M, Zivkovic S, Zein S, Shin WG. Simulation of DNA damage using Geant4-DNA: An overview of the molecularDNA example application. Precis Radiat Oncol. 2023 Jan;7(1):4-14.
26.     Sakata D, Lampe N, Karamitros M, Kyriakou I, Belov O, Bernal MA, et al. Evaluation of early radiation DNA damage in a fractal cell nucleus model using Geant4-DNA. Phys Med. 2019 Jun;62:152-157.
27.     Cunningham C, de Kock M, Engelbrecht M, Miles X, Slabbert J, Vandevoorde C. Radiosensitization effect of gold nanoparticles in proton therapy. Front Public Health. 2021; 9:699822.
28.     Lo CY, Tsai SW, Niu H, Chen FH, Hwang HC, Chao TC. Gold-nanoparticles-enhanced production of reactive oxygen species in cells at spread-out Bragg peak under proton beam radiation. ACS Omega. 2023 May;8(20):17922-17931.
29.     Cirrone GA, Cuttone G, Mazzaglia ES, Romano F, Sardina D, Agodi C, et al. Hadrontherapy: A Geant4-based tool for proton/ion-therapy studies. Prog Nucl Sci Technol. 2011;2:207-212.
30.     Jia SB, Romano F, Cirrone GA, Cuttone G, Hadizadeh MH, Mowlavi AA, et al. Designing a range modulator wheel to spread-out the Bragg peak for a passive proton therapy facility. Nucl Instrum Methods Phys Res A. 2016;806:101-108.
31.     Friedland W, Dingfelder M, Kundrát P, Jacob P. Track structures, DNA targets and radiation effects in the biophysical Monte Carlo simulation code PARTRAC. Mutat Res. 2011 Jan;711(1-2):28-40.
32.     Lampe N, Karamitros M, Breton V, Brown JM, Kyriakou I, Sakata D, et al. Mechanistic DNA damage simulations in Geant4-DNA part 1: A parameter study in a simplified geometry. Phys Med. 2018 Apr;48:135-145.
33.     Mortazavi SM, Rafiepour P, Mortazavi SA, Toosi SR, Shomal PR, Sihver L. Radium deposition in human brain tissue: A Geant4-DNA Monte Carlo toolkit study. Z Med Phys. 2024 Feb;34(1):166-174.
34.     Sakata D, Hirayama R, Shin WG, Belli M, Tabocchini MA, Stewart RD, et al. Prediction of DNA rejoining kinetics and cell survival after proton irradiation for V79 cells using Geant4-DNA. Phys Med. 2023;105:102508.
35.     Stewart RD. Two-lesion kinetic model of double-strand break rejoining and cell killing. Radiat Res. 2001 Oct;156(4):365-378.
36.     Elsässer T, Weyrather WK, Friedrich T, Durante M, Iancu G, Krämer M, et al. Quantification of the relative biological effectiveness for ion beam radiotherapy: Direct experimental comparison of proton and carbon ion beams and a novel approach for treatment planning. Int J Radiat Oncol Biol Phys. 2010 Nov;78(4):1177-1183.
37.     Zolghadri S, Rafiepour P, Yousefnia H. Quantifying DNA strand breaks from targeted alpha emitters 225Ac and 227Th via Geant4-DNA: Implications for RBE and cell survival. EJNMMI Phys. 2025;12(1):92.
38.     Sisin NN, Rashid RA, Abdullah R, Razak KA, Geso M, Akasaka H, et al. Gafchromic™ EBT3 film measurements of dose enhancement effects by metallic nanoparticles for 192Ir brachytherapy, proton, photon and electron radiotherapy. Radiation. 2022;2(1):130-148.
39.     Ahmad R, Royle G, Lourenço A, Schwarz M, Fracchiolla F, Ricketts K. Investigation into the effects of high-Z nanomaterials in proton therapy. Phys Med Biol. 2016 Jun;61(12):4537-4550.
40.     Rashid RA, Abidin SZ, Anuar MA, Tominaga T, Akasaka H, Sasaki R, et al. Radiosensitization effects and ROS generation by high-Z metallic nanoparticles on human colon carcinoma cell (HCT116) irradiated under 150 MeV proton beam. OpenNano. 2019;4:100027.
41.     Zwiehoff S, Johny J, Behrends C, Landmann A, Mentzel F, Bäumer C, et al. Enhancement of proton therapy efficiency by noble metal nanoparticles is driven by the number and chemical activity of surface atoms. Small. 2022 Mar;18(9).
42.     Wang CC, Hsiao YY, Lee CC, Chao TC, Wang CC, Tung CJ. Monte Carlo simulations of therapeutic proton beams for relative biological effectiveness of double-strand break. Int J Radiat Biol. 2012 Jan;88(1-2):158-163.
43.     Chaudhary P, Marshall TI, Currell FJ, Kacperek A, Schettino G, Prise KM, et al. Variations in the processing of DNA double-strand breaks along 60-MeV therapeutic proton beams. Int J Radiat Oncol Biol Phys. 2016 May;95(1):86-94.
44.     Liu Y, Zhu K, Peng X, Luo S, Zhu J, Xiao W, et al. Proton relative biological effectiveness for the induction of DNA double strand breaks based on Geant4. Biomed Phys Eng Express. 2024 May;10(3):035015.
 
 
Iranian Journal of Medical Physics
Volume 23, Issue 2 - Serial Number 2
March and April 2026
Pages 93-102

  • Receive Date 03 February 2026
  • Revise Date 11 March 2026
  • Accept Date 17 May 2026