Cellular dosimetry of beta emitting radionuclides-antibody conjugates for radioimmunotherapy

Document Type : Original Article


1 Department of Medical Physics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

2 Department of Radioisotope, Nuclear Science and Technology Research Institute, Tehran, Iran

3 Radiopharmaceutical Research and Development Laboratory, Nuclear Science and Technology Research Institute, Tehran, Iran

4 Faculty of Nuclear Engineering, Shahid Beheshti University, Tehran, Iran

5 Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran


Introduction: The choice of optimal radionuclides for radioimmunotherapy depends on several factors, especially the radionuclide and antibody. The dosimetric characteristics of a non-internalizing and an internalizing monoclonal antibody (MAb) labeled with beta emitting radionuclides were investigated.
Methods: Using Geant4-DNA Monte Carlo simulation, we carry out dosimetric calculations for different subcellular distributions of beta-emitting radionuclides; 131I, 177Lu, 64Cu, 186Re and 153Sm.
Results:The dependency of theradialdose profiles on the energy spectra of   electrons (beta particles and Auger and internal conversion electrons) and also their relative yield of emission is clear. The highest difference between the radionuclides tested was observed when the activity was localized in the nucleus. There was not considerable difference in the nucleus dose when radionuclides were localized in cytoplasm and over the cell membrane.
Conclusion: There is a very significant increase in the dose deposited to the nucleus if 153Sm localized at the nucleus. Although subcellular localization of activity isn’t a critical factor for beta emitting radionuclides, but the use of internalizing MAbs leads to an increase in nucleus dose and to the killing of single cells in addition to the tumors.


Main Subjects

  1. Koppe MJ, Postema EJ, Aarts F, Oyen WJ, Bleichrodt RP, Boerman OC. Antibody-guided radiation therapy of cancer. Cancer Metastasis Rev. 2005 Dec;24(4):539-67.
  2. Pouget JP, Navarro-Teulon I, Bardiès M, Chouin N, Cartron G, Pèlegrin A, Azria D. Clinical radioimmunotherapy--the role of radiobiology. Nat Rev Clin Oncol. 2011 Nov 8;8(12):720-34.
  3. Navarro-Teulon I, Lozza C, Pèlegrin A, Vivès E, Pouget JP. General overview of radioimmunotherapy of solid tumors. Immunotherapy. 2013 May;5(5):467-87.
  4. Pouget JP, Lozza C, Deshayes E, Boudousq V, Navarro-Teulon I. Introduction to radiobiology of targeted radionuclide therapy. Front Med (Lausanne). 2015 Mar 17;2:12.
  5. Tajik-Mansoury MA, Rajabi H, Mozdarani H. Cellular S-value of beta emitter radionuclide’s determined using Geant4 Monte Carlo toolbox, comparison to MIRD S-values. Iran J Nucl Med. 2016;24(1):37-45.
  6. Kassis AI. The amazing world of auger electrons. Int J Radiat Biol. 2004 Nov-Dec;80(11-12):789-803.
  7. Hindorf C, Emfietzoglou D, Lindén O, Bousis C, Fotopoulos A, Kostarelos K, Flux GD. Single-cell dosimetry for radioimmunotherapy of B-cell lymphoma patients with special reference to leukemic spread. Cancer Biother Radiopharm. 2007 Jun;22(3):357-66.
  8. Hartman T, Lundqvist H, Westlin JE, Carlsson J. Radiation doses to the cell nucleus in single cells and cells in micrometastases in targeted therapy with (131)I labeled ligands or antibodies. Int J Radiat Oncol Biol Phys. 2000 Mar 1;46(4):1025-36.
  9. Neti PV, Howell RW. Isolating effects of microscopic nonuniform distributions of (131)I on labeled and unlabeled cells. J Nucl Med. 2004 Jun;45(6):1050-8.
  10. Maramorosch K. Advances in cell culture. Elsevier; 1985. p. 261-268.
  11. Howell RW. Radiation spectra for Auger-electron emitting radionuclides: report No. 2 of AAPM Nuclear Medicine Task Group No. 6. Med Phys. 1992 Nov-Dec;19(6):1371-83.
  12. Eckerman KF, Endo A. MIRD: radionuclide data and decay schemes. The Society of Nuclear Medicine; 1989.
  13. Bousis C, Emfietzoglou D, Hadjidoukas P, Nikjoo H. Monte Carlo single-cell dosimetry of Auger-electron emitting radionuclides. Phys Med Biol. 2010 May 7;55(9):2555-72.
  14. Bousis C, Emfietzoglou D, Nikjoo H. Monte Carlo single-cell dosimetry of I-131, I-125 and I-123 for targeted radioimmunotherapy of B-cell lymphoma. Int J Radiat Biol. 2012 Dec;88(12):908-15.
  15. Fourie H, Newman RT, Slabbert JP. Microdosimetry of the Auger electron emitting 123I radionuclide using Geant4-DNA simulations. Phys Med Biol. 2015 Apr 21;60(8):3333-46.
  16. Hillyar CR1, Cornelissen B, Vallis KA. Uptake, internalization and nuclear translocation of radioimmunotherapeutic agents. Ther Deliv. 2014 Mar;5(3):319-35.
  17. Barendswaard EC, Humm JL, O'Donoghue JA, Sgouros G, Finn RD, Scott AM, Larson SM, Welt S. Relative therapeutic efficacy of (125)I- and (131)I-labeled monoclonal antibody A33 in a human colon cancer xenograft. J Nucl Med. 2001 Aug;42(8):1251-6.
  18. Behr TM, Sgouros G, Vougiokas V, Memtsoudis S, Gratz S, Schmidberger H, Blumenthal RD, Goldenberg DM, Becker W. Therapeutic efficacy and dose-limiting toxicity of Auger-electron vs. beta emitters in radioimmunotherapy with internalizing antibodies: evaluation of 125I- vs. 131I-labeled CO17-1A in a human colorectal cancer model. Int J Cancer. 1998 May 29;76(5):738-48.
  19. Paquet F, Barbey P, Bardiès M, Biau A, Blanchardon E, Chetioui A, Lebaron-Jacobs L, Pasquier JL. The assessment and management of risks associated with exposures to short-range Auger- and beta-emitting radionuclides. State of the art and proposals for lines of research. J Radiol Prot. 2013 Mar;33(1):R1-16.
  20. Bishayee A, Rao DV, Bouchet LG, Bolch WE, Howell RW. Protection by DMSO against cell death caused by intracellularly localized iodine-125, iodine-131 and polonium-210. Radiat Res. 2000 Apr;153(4):416-27.
  21. Behr TM, Béhé M, Löhr M, Sgouros G, Angerstein C, Wehrmann E, Nebendahl K, Becker W. Therapeutic advantages of Auger electron- over beta-emitting radiometals or radioiodine when conjugated to internalizing antibodies. Eur J Nucl Med. 2000 Jul;27(7):753-65.
  22. Bryan JN1, Jia F, Mohsin H, Sivaguru G, Miller WH, Anderson CJ, Henry CJ, Lewis MR. Comparative uptakes and biodistributions of internalizing vs. noninternalizing copper-64 radioimmunoconjugates in cell and animal models of colon cancer. Nucl Med Biol. 2005 Nov;32(8):851-8.
  23. Hens M, Vaidyanathan G, Welsh P, Zalutsky MR. Labeling internalizing anti-epidermal growth factor receptor variant III monoclonal antibody with (177)Lu: in vitro comparison of acyclic and macrocyclic ligands. Nucl Med Biol. 2009 Feb;36(2):117-28.
  24. Sastry K, Haydock C, Basha A, Rao D. Electron dosimetry for radioimmunotherapy: optimal electron energy. Radiat Prot Dosimetry. 1985;13(1-4):249-252.
  25. Mattes MJ. Radionuclide-antibody conjugates for single-cell cytotoxicity. Cancer. 2002 Feb 15;94(4 Suppl):1215-23.