A comparative evaluation of Ac225 vs Bi213 as therapeutic radioisotopes for targeted alpha therapy for cancer

  • Barry J. Allen
Scientific Paper


The Ac225:Bi213 generator is the mainstay for preclinical and clinical studies of targeted alpha therapy for cancer. Both Ac225 (four alpha decays) and Bi213 (one alpha decay) are being used to label targeting vectors to form the alpha immunoconjugate for cancer therapy. This paper considers the radiobiological and economic aspects of Ac225 vs Bi213 as the preferred radioisotope for preclinical and clinical TAT. The in vitro and in vivo evidence and the role of DNA repair processes is examined. The maximum tolerance dose and therapeutic gain are endpoints for comparison. Ac225 has the higher therapeutic gain, when normalised to equal alpha production. However, the slow repair of double strand breaks reduces this advantage. Comparisons are made for the specific energy deposition in targeted and non-targeted cells, for endothelial cells by direct or indirect targeting, the need for sparing agents to save critical organs and cost considerations for preclinical and clinical trials and clinical use. Overall, Ac225 is found to have the better or equal performance to Bi213 at a much lower cost.


Targeted alpha therapy Cancer Therapeutic radioisotopes Bi213 Ac225 DSB repair Cell survival Specific activity Anti-vascular therapy Maximum tolerance dose 



My thanks for e-discussions with George Sgouros and Alfred Morgenstern.

Compliance with ethical standards

Conflict of interest

The author declares that he has no conflict of interest.

Ethical approval

There are neither animal nor human experiments in this publication.


  1. 1.
    Allen BJ, Raja C, Rizvi SMA, Song EY, Graham P (2007) Tumour anti-vascular alpha therapy: a mechanism for the regression of solid tumours in metastatic cancer. Phys Med Biol 52:L15–L19CrossRefPubMedGoogle Scholar
  2. 2.
    Allen BJ, So T, Rizv SMA, Song EY, Fernandez HR, Lutz-Mann L. Mutagenesis induced by targeted alpha therapy using 213Bi-cDTPA-9.2.27 in lac Z transgenic mice. Cancer Biol Therapy (2009): 8, 9, 777–781Google Scholar
  3. 3.
    Antonelli F et al (2015) Induction and Repair of DNA DSB as Revealed by H2AX Phosphorylation Foci in Human Fibroblasts exposed to low and high-LET radiation: relationship with early and delayed reproductive cell death. Radiat Research 183(4):417–431. doi: 10.1667/RR13855.1 CrossRefGoogle Scholar
  4. 4.
    Antczak C, Jaspreet S. Jaggi Clare V. LeFave Michael J. Curcio Michael R. McDevitt David A. Scheinberg D Influence of the linker on the biodistribution and catabolism of actinium-225 self-immolative tumor-targeted isotope generators. Bioconjug Chem. 2006; 17(6): 1551–1560. doi: 10.1021/bc060156+ CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Barendson GW. Dose survival curves of human cells in tissue culture irradiated with alpha, beta, 20 kV and 200 kV X-radiation. Nature 1962 1153–1155Google Scholar
  6. 6.
    Borchardt P, Yuan RR, Miederer M, McDevitt MR, Scheinberg DA (2003) Targeted Ac225 in vivo generators for therapy of ovarian cancer. Cancer Res 63:5084–5090PubMedGoogle Scholar
  7. 7.
    Essler M, Gärtner FC, Neff F et al (2012) Eur J Nucl Med Mol Imaging 39:602. doi: 10.1007/s00259-011-2023-6 CrossRefPubMedGoogle Scholar
  8. 8.
    Huang KT, Chen YH, Walker AM (2004) Inaccuracies in MTS assays: major distortion effects of medium, serum albumin and fatty acids. Biotechniques 37:406–422PubMedGoogle Scholar
  9. 9.
    Huang CY, UNSW PhD thesis; Monte Carlo modelling of targeted alpha therapy from single cell to tumour. 2012Google Scholar
  10. 10.
    Huang CY, Oborn BM, Guatelli S, Allen BJ (2012) Monte Carlo calculation of the maximum therapeutic gain of Tumor Anti-vascular Alpha Therapy. Med Phys 39(3):1282–1288CrossRefPubMedGoogle Scholar
  11. 11.
    Jurcic JG, S.M. Larson, G. Sgouros, M.R. McDevitt, R.D. Finn, C.R. Divgi Å.M. Ballangrud, K.A., Hamacher, D. Ma, Humm JL (2002) Targeted α particle immunotherapy for myeloid leukemia. Blood 100:1233–1239PubMedGoogle Scholar
  12. 12.
    Kratochwil C, Giesel F, Bruchertseifer F, Meir W, Apostolidis C, Boll R, Murphy F, Haberkorn U, Morgenstern A. 213Bi-.ATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience. Eur J Nucl Med Mol Imaging. 2014 41 2106–2119CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Kratochwil C, F. Giesel, F. Bruchertseifer, M. Rius, C. Apostolidis, U. Haberkorn, A. Morgenstern. Ac-225-PSMA617: a single center experience of 40 patients receiving PSMA-targeted alpha therapy. Soc Nucl Med 2016 doi: 10.2967/jnumed.116.178673 Google Scholar
  14. 14.
    Lindmo T, Boven E, Mitchell JB, Morstyn G, Bumm PA (1985) Specific killing of human melanoma cells by I125labeled 9.2.27 monoclonal antibody. Cancer Res 45:5080–5087PubMedGoogle Scholar
  15. 15.
    Kratochwil C, Bruchertseifer F, Giesel F, Apostolidis C, Haberkorn U, Morgenstern A. Ac-225-dotatoc – dose finding for alpha particle emitter based radionuclide therapy of neuroendocrine tumors. Eur J Nucl Med Mol Imaging 2015 42, s1, p. s36
  16. 16.
    Kruiff RM de, Wolterbeck HT D en kova AG (2015) A critical review of alpha radionuclide therapy-how to deal with recoiling daughters? Pharmaceutical 8:321–336Google Scholar
  17. 17.
    McDevitt MR, Ma D, Lai LT et al (2001) Tumor therapy with targeted atomic nanogenerators. Science 294:1537–1540CrossRefPubMedGoogle Scholar
  18. 18.
    McDevitt MR, Scheinberg DA (2002) Ac-225 and her daughters: the many faces of Shiva. Cell Death Differ 9:593–594. doi: 10.1038/sj/cdd/4401047 CrossRefPubMedGoogle Scholar
  19. 19.
    Miederer M, McDevitt M, Borchadt P et al. Treatment of neuroblasoma meningeal carcinomatosis with intrathecal application of alpha emitting atomic nanogenerators targeting disialo-Ganglioside GD2. Clin Cancer Res 2004, 10, 6985–92CrossRefPubMedGoogle Scholar
  20. 20.
    Olive PL, Banáth JP, Durand RE. Heterogeneity in radiation-induced DNA damage and repair in tumor and normal cells measured using the “comet” assay. Radiation Res 1990, 122, 1, 86–94CrossRefPubMedGoogle Scholar
  21. 21.
    Raja C, Graham P, Rizvi SMA, Song E, Goldsmith H, Thompson J, Bosserhoff A, Morgenstern A, Apostolidis C, Kearsley JH, Reisfeld R, Allen BJ. Interim analysis of toxicity and response in Phase 1 trial of systemic targeted alpha therapy for metastatic melanoma. Cancer Biol Ther. 2007 6:6, 846–52CrossRefPubMedGoogle Scholar
  22. 22.
    Rizvi SMA, Sarkar S, Goozee G, Allen BJ (2000) Radio-immunoconjugates for Targeted Alpha Therapy of Malignant Melanoma. Melanoma Res 10:281–289CrossRefGoogle Scholar
  23. 23.
    Roeske JC, Stinchcomb TG. 2006, The average number of alpha-particle hits to the cell nucleus required to eradicate a tumour cell population. Phys. Med. Biol. 51 N179Google Scholar
  24. 24.
    Suliman G, Pommé S, Marouli M, Van Ammel R, Stroh H, Jobbágy V, Paepen J, Dirican A, Bruchertseifer F, Apostolidis C, Morgenstern A (2013) Half-lives of 221Fr, 217At, 213Bi, 213Po and 209Pb from the 225Ac decay series. Appl Radiat Isot 77:32–37CrossRefPubMedGoogle Scholar
  25. 25.
    Song EY, Rizvi SMA, Raja C, Qu CF, Yuen J, Morgenstern A, Apostolidis C, Allen BJ (2008) The cytokinesis–block assay as a biological dosimeter for targeted alpha therapy. Phys Med Biol 53:319–328CrossRefPubMedGoogle Scholar
  26. 26.
    Song H, Hobbs RF, Vajravelu R, Huso DL, Esalas C, Apostolidis C, Morgenstern A, Sgouros G (2009) Radioimmuunotherapy of breast cancer metastases with alpha particle emitter Ac225; comparing efficacy with 213Bi, 90Y. Cancer Res 69(23):8941–8948CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Tabrizi MA, Tseng CM, Roskos LK. Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discovery Today 2006, 11, 1/2, 81–88Google Scholar

Copyright information

© Australasian College of Physical Scientists and Engineers in Medicine 2017

Authors and Affiliations

  1. 1.Faculty of MedicineUniversity Western SydneySydneyAustralia

Personalised recommendations