Alpha Radionuclide Therapy

  • F. F. (Russ) Knapp
  • Ashutosh Dash


Therapeutic applications of alpha (α)-emitting radionuclides were introduced soon after the isolation of radium from pitch blende by Marie Curie in the early twentieth century. Because of the very high linear energy transfer (LET), α-emitters can be very lethal and result in very effective cell killing sterilization if the α-decay commences at the cellular target site. With recent innovations in cancer cell targeting with antibodies and peptides and rapid targeting strategies, the efficacy of several radiopharmaceuticals to which α-emitters have been attached has been demonstrated. In particular, the effectiveness of pain management has recently demonstrated with 223Ra chloride (Xofigo®) in patients with hormone refractory skeletal metastases from prostate cancer. This chapter discusses various α-emitting radionuclides for therapy and several interesting applications.


International Atomic Energy Agency Alpha Particle Linear Energy Transfer Relative Biological Effectiveness Radionuclide Therapy 


  1. Abbas N, Heyerdahl H, Bruland OS, et al. Experimental α-particle radioimmunotherapy of breast cancer using 227Th-labeled p-benzyl-DOTA-trastuzumab. EJNMI Research. 2011.
  2. Abbas N, Bruland ØS, Brevik EM, et al. Preclinical evaluation of 227Th-labeled and 177Lu-labeled trastuzumab in mice with HER-2-positive ovarian cancer xenografts. Nucl Med Commun. 2012;33:838–47.PubMedCrossRefGoogle Scholar
  3. Allen BJ. Future prospects for targeted alpha therapy. Curr Radiopharm. 2011;4(4):336–42.PubMedCrossRefGoogle Scholar
  4. Apostolidis C, Molinet R, McGinley J, et al. Cyclotron production of Ac-225 for targeted alpha therapy. Appl Radiat Isot. 2005;62:383–7.PubMedCrossRefGoogle Scholar
  5. Atcher RW, Friedman AM, Hines JJ. An improved generator for the production of 212Pb and 212Bi from Ra. Int J Rad Appl Instrum A. 1988;39:283–6.PubMedCrossRefGoogle Scholar
  6. Azure MT, Archer RD, Sastry KSR, et al. Biological effect of lead-212 localized in the nucleus of mammalian cells: role of recoil energy in the radiotoxicity of internal alpha-particle emitters biological effect of lead-212 localized in the nucleus of mammalian cells: role of recoil energy in the radiotoxicity of internal alpha-particle emitters. Radiat Res. 1994;140:276–83.PubMedCrossRefPubMedCentralGoogle Scholar
  7. Bardiès M. Dosimetry and microdosimetry of targeted radiotherapy. Curr Pharm Des. 2000;6:1469–502.PubMedCrossRefGoogle Scholar
  8. Barendsen GW, Koot CJ, Van Kersen GR, et al. The effect of oxygen on impairment of the proliferative capacity of human cells in culture by ionizing radiations of different LET. Int J Radiat Biol Relat Stud Phys Chem Med. 1966;10:317–27.PubMedCrossRefGoogle Scholar
  9. Bertrand A, Legras B, Martin J. Use of radium-224 in the treatment of ankylosing spondylitis and rheumatoid synovitis. Health Phys. 1978;35:57–60.PubMedCrossRefGoogle Scholar
  10. Beyer GJ, Comor J, Dakovic M, et al. Production routes of the alpha emitting 149Tb for medical application. Radiochim Acta. 2002;90:247–52.CrossRefGoogle Scholar
  11. Beyer GJ, Miederer M, Vranjes-Duric S, et al. Targeted alpha therapy in vivo: direct evidence for single cancer cell kill using 149Tb-rituximab. Eur J Nucl Med Mol Imaging. 2004;31:547–54.PubMedCrossRefGoogle Scholar
  12. Bolch WE, Eckerman KF, Sgouros G, et al. MIRD pamphlet No. 21: a generalized schema for radiopharmaceutical dosimetry-standardization of nomenclature. J Nucl Med. 2009;50:477–84.PubMedCrossRefGoogle Scholar
  13. Boll RA, Malkemus D, Mirzadeh S. Production of actinium-225 for alpha particle mediated radioimmunotherapy. Appl Radiat Isot. 2005;62:667–79.PubMedCrossRefGoogle Scholar
  14. Bomanji JB, Wong W, Gaze MN, Cassoni A, Waddington W, Solano J, Ell PJ. Treatment of neuroendocrine tumours in adults with 131I-MIBG therapy. Clin Oncol. 2003;15:193–8.CrossRefGoogle Scholar
  15. Brechbiel MW. Targeted alpha-therapy: past, present, future? Dalton Trans. 2007;2(43):4918–28.CrossRefGoogle Scholar
  16. Brown I, Carpenter RN. At a-particle radiotherapy for undifferentiated thyroid cancer. Acta Radiol Suppl. 1991;376:174–5.PubMedGoogle Scholar
  17. Carlin S, Akabani G, Zalutsky MR. In vitro cytotoxicity of (211At)-astatide and (131)I-iodide to glioma tumor cells expressing the sodium/iodide symporter. J Nucl Med. 2003;44:1827.PubMedGoogle Scholar
  18. Chappell LL, Deal KA, Dadachova E, et al. Synthesis, conjugation, and radiolabeling of a novel bifunctional chelating agent for 225Ac radioimmunotherapy applications. Bioconjug Chem. 2000;11:510–9.PubMedCrossRefGoogle Scholar
  19. Chouin N, Bardies M. Alpha-particle microdosimetry. Curr Radiopharm. 2011;4(3):266–80.PubMedCrossRefGoogle Scholar
  20. Dahle J, Borrebaek J, Melhus KB, et al. Initial evaluation of (227)Th-p-benzyl-DOTA-rituximab for low-dose rate alpha-particle radioimmunotherapy. Nucl Med Biol. 2006;33:271–9.PubMedCrossRefGoogle Scholar
  21. Essler M, Gartner FC, Neff F, et al. Therapeutic efficacy and toxicity of 225Ac-labelled vs. 213Bi-labelled tumour-homing peptides in a preclinical mouse model of peritoneal carcinomatosis. Eur J Nucl Med Mol Imaging. 2012;39:602–12.PubMedCrossRefGoogle Scholar
  22. Friesen C, Roscher M, Hormann I, et al. Anti-CD33-antibodies labelled with the alpha emitter Bismuth-213 kill CD33-positive acute myeloid leukaemia cells specifically by activation of caspases and break radio- and chemoresistance by inhibition of the anti-apoptotic proteins X-linked inhibitor of apoptosis protein and B-cell lymphoma-extra large. Eur J Cancer. 2013;49:2542–54.PubMedCrossRefGoogle Scholar
  23. Goodhead DT. Initial events in the cellular effects of ionizing radiations: clustered damage in DNA. Int J Radiat Biol. 1994;65:7–17.PubMedCrossRefGoogle Scholar
  24. Hall EJ. Radiobiology for the radiologist. 4th ed. Philadelphia: JB Lippincott Company; 1994.Google Scholar
  25. Hauck ML, Larsen RH, Welsh PC, et al. Cytotoxicity of a-particle emitting 211At-labeled antibody in tumor spheroids: no effect of hyperthermia. Br J Cancer. 1998;77:753.PubMedCrossRefPubMedCentralGoogle Scholar
  26. Henriksen G, Messelt S, Olsen E, Larsen RH. Optimization of cyclotron production parameters for the 209Bi(α,2n)211At reaction related to biomedical use of 211At. Appl Radiat Isot. 2001;54:829–34.CrossRefGoogle Scholar
  27. Heyerdahl H, Abbas N, Sponheim K, et al. Targeted alpha therapy with 227Th-trastuzumab of intraperitoneal ovarian cancer in nude mice. Curr Radiopharm. 2013;6(2):106–16.PubMedCrossRefGoogle Scholar
  28. Holden CS, Schenter RE. Production of actinium-227 and thorium-228 from radium-226 to supply alpha-emitting isotopes radium-223, thorium-227, radium-224, bismuth-212. 2014.US 20140226774.
  29. Howell RW, Goddu SM, Narra VR, et al. Radiotoxicity of gadolinium-148 and radium-223 in mouse testes: relative biological effectiveness of alpha-particle emitters in vivo. Radiat Res. 1997;147:342–8.PubMedCrossRefPubMedCentralGoogle Scholar
  30. Humm JL, Cobb LM. Nonuniformity of tumor dose in radioimmunotherapy. J Nucl Med. 1990;31:75–83.PubMedGoogle Scholar
  31. IAEA Technical Report SeriEs 15. A basic toxicity classification of radionuclides. 1963.
  32. IAEA Technical Report Series 468. Cyclotron produced radioisotopes: physical characteristics and production methods. 2009.
  33. Jurcic JG. Targeted alpha-particle immunotherapy with bismuth-213 and actinium-225 for acute myeloid leukemia. J Postgrad Med Edu Res. 2013;47(1):14–7.CrossRefGoogle Scholar
  34. Jurcic JG, Larson SM, Sgouros G, et al. Targeted alpha particle immunotherapy for myeloid leukemia. Blood. 2002;100:1233–9.PubMedGoogle Scholar
  35. Kennel SJ, Mirzadeh S. Vascular targeted radioimmunotherapy with 213Bi – an alpha-particle emitter. Nucl Med Biol. 1998;25:241–6.PubMedCrossRefGoogle Scholar
  36. Kennel SJ, Boll R, Stabin M, et al. Radioimmunotherapy of micrometastases in lung with vascular targeted 213Bi. Br J Cancer. 1999;80:175–84.PubMedCrossRefPubMedCentralGoogle Scholar
  37. Kennel SJ, Chappell LL, Dadachova K, et al. Evaluation of 225Ac for vascular targeted radioimmunotherapy of lung tumors. Cancer Biother Radiopharm. 2000;15:235–44.PubMedCrossRefGoogle Scholar
  38. Koch L, Apostolidis C, Janssens W, et al. Production of Ac-225 and application of the Bi-213 daughter in cancer therapy. Czech J Phys. 1999;49:817–22.CrossRefGoogle Scholar
  39. Lebeda O, Jiran R, Rális J, et al. A new internal target system for production of 211At on the cyclotron U-120M. Appl Radiat Isot. 2005;63:49–53.PubMedCrossRefGoogle Scholar
  40. Lorimore SA, Kadhim MA, Pocock DA, et al. Chromosomal instability in the descendants of unirradiated surviving cells after alpha-particle irradiation. Proc Natl Acad Sci U S A. 1998;95:5730–3.PubMedCrossRefPubMedCentralGoogle Scholar
  41. Lundh C, Lindencrona U, Schmitt A, et al. Biodistribution of free 211At and 125I- in nude mice bearing tumors derived from anaplastic thyroid carcinoma cell lines. Cancer Biother Radiopharm. 2006;21:591–600.PubMedCrossRefGoogle Scholar
  42. Macklis RM. The great radium scandal. Sci Am. 1993;269:94–9.PubMedCrossRefGoogle Scholar
  43. Metting NF, Palayoor ST, Macklis RM. Induction of mutations by bismuth-212 alpha particles at two genetic loci in human B-lymphoblasts. Radiat Res. 1992;132:339–45.PubMedCrossRefGoogle Scholar
  44. Metzenbaum M. Radium: Its value in the treatment of lupus, rodent ulcer, and epithelioma, with reports of cases. Int Clin (JB Lippincott). 1905;4(14):21–31.Google Scholar
  45. Miederer M, Scheinberg DA, McDevitt MR. Realizing the potential of the Actinium-225 radionuclide generator in targeted alpha-particle therapy applications. Adv Drug Deliv Rev. 2008;60(12):1371–82.PubMedCrossRefPubMedCentralGoogle Scholar
  46. Montavon G, Le Du A, Champion J, et al. DTPA complexation of bismuth in human blood serum. Dalton Tran. 2012;41(28):8615–23.CrossRefGoogle Scholar
  47. Mulford D, Scheinberg DA, Jurcic JG. The promise of targeted α-particle therapy. J Nucl Med. 2005;46(1):199S–204.PubMedGoogle Scholar
  48. Murud KM, Larsen RH, Bruland OS, Hoff P. Influence of pretreatment with 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (APB) on organ uptake of 211At and I-labeled amidobisphosphonates in mice. Nucl Med Biol. 1999a;26:791–4.PubMedCrossRefGoogle Scholar
  49. Murud KM, Larsen RH, Hoff P, et al. Synthesis, purification, and in vitro stability of 211At- and 125I-labeled amidobisphosphonates. Nucl Med Biol. 1999b;26:397–403.PubMedCrossRefGoogle Scholar
  50. Nicolini M, Mazzi U. Therapeutic potential of alpha-emitters: chemistry to biology to clinical applications. Padova: SGE Editorali; 1999.Google Scholar
  51. Ning L, Jiannan J, Shangwu M, et al. Preparation and preliminary evaluation of astatine-211 labeled IgG via DTPA anhydride. J Radiol Nucl Chem. 1998;227:187–90.CrossRefGoogle Scholar
  52. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369:213–23.PubMedCrossRefGoogle Scholar
  53. Petrich T, Quintanilla-Martinez L, Korkmaz Z, et al. Effective cancer therapy with the alpha-particle emitter [211At]astatine in a mouse model of genetically modified sodium/iodide symporter-expressing tumors. Clin Cancer Res. 2006;15(12):1342–8.CrossRefGoogle Scholar
  54. Pouget JP, Mather SJ. General aspects of the cellular response to low- and high-LET radiation. Eur J Nucl Med. 2001;28:541–61.PubMedCrossRefGoogle Scholar
  55. Proescher F. The intravenous injection of soluble radium salts in men. Radium. 1913;1:9–10.Google Scholar
  56. Rosenblat TL, McDevitt MR, Mulford DA, et al. Sequential cytarabine and alpha-particle immunotherapy with bismuth-213-lintuzumab (HuM195) for acute myeloid leukemia. Clin Cancer Res. 2010;16:5303–11.PubMedCrossRefPubMedCentralGoogle Scholar
  57. Schales F. Brief history of Ra-224 usage in radiotherapy and radiobiology. Health Phys. 1978;35:25–32.CrossRefGoogle Scholar
  58. Schwarz UP, Plascjak P, Beitzel MP, et al. Preparation of 211At labeled humanized anti-tac using 211At produced in disposable internal and external bismuth targets. Nucl Med Biol. 1998;25:89–93.PubMedCrossRefGoogle Scholar
  59. Sgouros G, Finn RD, Humm JL. Radioimmunotherapy with alpha-emitting nuclides. Eur J Nucl Med. 1998;25(9):1341–51.PubMedCrossRefGoogle Scholar
  60. Sgouros G, Roeske JC, McDevitt MR, et al. SNM MIRD Committee, Bolch WE, Brill AB, Fisher DR, Howell RW, Meredith RF, Sgouros G, Wessels BW, Zanzonico PB. MIRD Pamphlet No. 22 (abridged): radiobiology and dosimetry of alpha-particle emitters for targeted radionuclide therapy. J Nucl Med. 2010;51:311–28.Google Scholar
  61. Sgouros G, Hobbs RF, Song H. Modelling and dosimetry for alpha-particle therapy. Curr Radiopharm. 2011;4(3):261–5.PubMedCrossRefPubMedCentralGoogle Scholar
  62. Song H, Hobbs RF, Vajravelu R, et al. Radioimmunotherapy of breast cancer metastases with alpha-particle emitter 225Ac: comparing efficacy with 213Bi and 90Y. Cancer Res. 2009;69:8941–8.PubMedCrossRefPubMedCentralGoogle Scholar
  63. Vaidyanathan G, Zalutsky MR. Astatine radiopharmaceuticals: prospects and problems. Curr Radiopharm. 2008;1:177–96.PubMedCrossRefPubMedCentralGoogle Scholar
  64. Vaidyanathan G, Strickland DK, Zalutsky MR. Meta-[211At]astatobenzylguanidine: further evaluation of a potential therapeutic agent. Int J Cancer. 1994;15(57):908–13.CrossRefGoogle Scholar
  65. Vaidyanathan G, Affleck D, Welsh P, et al. Radioiodination and astatination of octreotide by conjugation labelling. Nucl Med Biol. 2000;27:329–37.PubMedCrossRefGoogle Scholar
  66. Vaidyanathan G, Boskovitz A, Shankar S, et al. Radioiodine and 211At-labeled guanidinomethyl halobenzoyl octreotate conjugates: potential peptide radiotherapeutics for somatostatin receptor-positive cancers. Peptides. 2004;25(12):2087–97.PubMedCrossRefGoogle Scholar
  67. Visser GWM, Diemer EL, Vo CM, et al. The biological behaviour of some organic astatine compounds in rats. Int J Appl Radiat Isot. 1981;32:913–7.PubMedCrossRefGoogle Scholar
  68. Wang H, Liu S, Zhang P, Zhang S, Naidu M, Wang Y. S-phase cells are more sensitive to high-linear energy transfer radiation. Int J Radiat Oncol Biol Phys. 2009;74:1236–41.PubMedCrossRefGoogle Scholar
  69. Wessels BW, Rogus RD. Radionuclide selection and model absorbed dose calculations for radiolabeled tumor associated antigens. Med Phys. 1984;11:638–45.PubMedCrossRefGoogle Scholar
  70. Zalutsky MR, Narula AS. Astatination of proteins using an N-succinimidyl tri-n-butylstannyl benzoate intermediate. Int J Rad Appl Instrum A. 1988;39:227–32.PubMedCrossRefGoogle Scholar
  71. Zalutsky MR, Pruszynski M. Astatine-211 Production and availability. Curr Radiopharm. 2011;4:177–85.PubMedCrossRefPubMedCentralGoogle Scholar
  72. Zalutsky MR, Vaidyanathan G. Astatine-211-labeled radiotherapeutics: an emerging approach to targeted alpha-particle radiotherapy. Curr Pharm Des. 2000;6(14):1433–55.PubMedCrossRefGoogle Scholar
  73. Zalutsky MR, Reardon DA, Akabani G, et al. Clinical experience with α-particle–emitting 211At: treatment of recurrent brain tumor patients with 211At-labeled chimeric antitenascin monoclonal antibody 81C6. J Nucl Med. 2008;49:30–8.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer India 2016

Authors and Affiliations

  • F. F. (Russ) Knapp
    • 1
  • Ashutosh Dash
    • 2
  1. 1.Nuclear Security and Isotope DivisionOak Ridge National LaboratoryOAK RIDGEUSA
  2. 2.Isotope Production and Applications DivisionBhabha Atomic Research CentreMumbaiIndia

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