Targeted Oncology

, Volume 13, Issue 2, pp 189–203 | Cite as

Alpha-Emitters and Targeted Alpha Therapy in Oncology: from Basic Science to Clinical Investigations

  • Mehran Makvandi
  • Edouard Dupis
  • Jonathan W. Engle
  • F. Meiring Nortier
  • Michael E. Fassbender
  • Sam Simon
  • Eva R. Birnbaum
  • Robert W. Atcher
  • Kevin D. John
  • Olivier Rixe
  • Jeffrey P. Norenberg
Review Article

Abstract

Alpha-emitters are radionuclides that decay through the emission of high linear energy transfer α-particles and possess favorable pharmacologic profiles for cancer treatment. When coupled with monoclonal antibodies, peptides, small molecules, or nanoparticles, the excellent cytotoxic capability of α-particle emissions has generated a strong interest in exploring targeted α-therapy in the pre-clinical setting and more recently in clinical trials in oncology. Multiple obstacles have been overcome by researchers and clinicians to accelerate the development of targeted α-therapies, especially with the recent improvement in isotope production and purification, but also with the development of innovative strategies for optimized targeting. Numerous studies have demonstrated the in vitro and in vivo efficacy of the targeted α-therapy. Radium-223 (223Ra) dichloride (Xofigo®) is the first α-emitter to have received FDA approval for the treatment of prostate cancer with metastatic bone lesions. There is a significant increase in the number of clinical trials in oncology using several radionuclides such as Actinium-225 (225Ac), Bismuth-213 (213Bi), Lead-212 (212Pb), Astatine (211At) or Radium-223 (223Ra) assessing their safety and preliminary activity. This review will cover their therapeutic application as well as summarize the investigations that provide the foundation for further clinical development.

Abbreviations

2B–DOTA-NCS

2-(p-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaceticacid

AIC

Alpha Immunoconjugate

BNL

Brookhaven National Laboratory

BLIP

Brookhaven Linac Isotope Producer

C-DEPA

1, 7-[2-(bis-carboxymethyl-amino)-ethyl]-4,10-biscarboxymethyl-1,4,7,10-tetraaza-cyclododec-1-yl-acetic acid

CHX-A-DTPA

cyclohexyl diethylenetriaminepentaacetic acid

DMP

2,3-Dimercapto-1-propanesulfonic acid

DMSA

Dimercaptosuccinic acid

DOTA

1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaceticacid

DOTA-SCN

4-isothiocyanate-benzyl 1,4,7,10-tetraazacyclododecane-N′, N″, N″’,N″” tetraacetic acid

DOTATOC

2-[4-[2-[[(2R)-1-[[(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-4-[[(2R,3R)-1,3-dihydroxybutan-2-yl]carbamoyl]-7-[(1R)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicos-19-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]-7,10-bis(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetic acid

DOTMP

1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonic

DOTPA

1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrapropionic acid

DTPA

diethylenetriaminepentaaceticacid

EDTA

2-({2-[Bis(carboxymethyl)amino]ethyl}(carboxymethyl)amino)acetic acid

FcRn

Neonatal Fc Receptors

HEHA-NCS

2-(4-isothiocyanatobenzyl)-1,4,7,10,13, 16-hexaazacyclohexadecane- 1,4,7,10,13,16hexaacetic acid

HPLC

High Pressure Liquid Chromatography

IAEA

International Atomic Energy Association

IPF

Isotope Production Facility

LANL

Los Alamos National Laboratory

LANSCE

Los Alamos National Laboratory Neutron Sciences Center

LET

Linear Energy Transfer

MeO-DOTA-NCS

a-(5-isothiocyanato-2-methoxyphenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaceticacid

MIA

Melanoma Inhibitory-Activity

MIRD

Medical Internal Radiation Dosimetry

NSACI

Nuclear Science Advisory Committee

ORNL

Oak Ridge National Laboratories

PEPA

1,4,7,10,13-pentaazacyclpentadecane-N, N, N, N, N pentaacetic acid

PRRT

Peptide Receptor Radiation Therapy

RBE

Relative Biological Effectiveness

RIT

Radio Immuno Therapy

TAT

Targeted Alpha Therapy

TCMC

2-(4-isothiocyanotobenzyl)-1, 4, 7, 10-tetraaza-1, 4, 7, 10-tetra-(2-carbamonyl methyl)-cyclododecane

TETPA

1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetrapropionic acid

TETA

1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid

Notes

Compliance with Ethical Standards

Funding

None.

Conflict of Interest

Olivier Rixe has received honorarium as a member of a scientific committee from Areva Med. All other authors declare no conflict of interest.

References

  1. 1.
    Milenic DE, Brechbeil MW. Targeting of radio-isotopes for cancer therapy. Cancer Biol Ther. 2004;3(4):361–70.PubMedCrossRefGoogle Scholar
  2. 2.
    McDevitt MR, Sgouros G, Finn RD, Humm JL, Jurcic JG, Larson SM, et al. Radioimmunotherapy with alpha-emitting nuclides. Eur J Nucl Med. 1998;25(9):1341–51.PubMedCrossRefGoogle Scholar
  3. 3.
    Munro TR. Relative radiosensitivity of nucleus and cytoplasm of Chinese hamster fibroblasts. Radiat Res. 1970;42(3):451–70.PubMedCrossRefGoogle Scholar
  4. 4.
    Nikula TK, McDevitt MR, Finn RD, Wu C, Kozak RW, Garmestani K, et al. Alpha-emitting bismuth cyclohexylbenzyl DTPA constructs of recombinant humanized anti-CD33 antibodies: pharmacokinetics, bioactivity, toxicity and chemistry. J Nucl Med. 1999;40(1):166–76.PubMedGoogle Scholar
  5. 5.
    Barendsen GW. Modification of radiation damage by fractionation of the dose, anoxia, and chemical protectors in relation to LET. Ann NY Acad Sci. 1964;114:96–114.PubMedCrossRefGoogle Scholar
  6. 6.
    Nuclear Science Advisory Committee. One of two charges to NSAC on the National Isotopes Production and Applications Program. Compelling research opportunities using isotopes. Final report. 2009.Google Scholar
  7. 7.
    International Atomic Energy Agency. INDC international nuclear data committee. Improvements in charged-particle monitor Ractions and nuclear data for medical isotope production. Vienna: IAEA; 2011.Google Scholar
  8. 8.
    Meredith RF, Torgue J, Azure MT, Shen S, Saddekni S, Banaga E, et al. Pharmacokinetics and imaging of 212Pb-TCMC-trastuzumab after intraperitoneal administration in ovarian cancer patients. Cancer Biother Radiopharm. 2014;29(1):12–7.  https://doi.org/10.1089/cbr.2013.1531.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Grimes WR. Chemical Research and Development for molten-salt breeder reactors. Oak Ridge: Report, ORNL-TM-1853; 1967.CrossRefGoogle Scholar
  10. 10.
    Norenberg J, Stables P, Atcher R, Tribble R, Faught J, Riedinger L. Workshop on the nation’s need for isotopes: present and future. Rockville: U.S. DOE/SC; 2008. p. 22.Google Scholar
  11. 11.
    Morgenstern A, Bruchertseifer F, Apostolidis. Bismuth-213 and Actinium-225 – generator performance and evolving therapeutic applications of two generator-derived alpha-emitting radioisotopes. Curr Radiopharm. 2012;(5):221–7.Google Scholar
  12. 12.
    Boll RA, Mirzadeh S, Kennel SJ, DePaoli DW, Webb OF. Bi-213 for alpha-particle-mediated radioimmunotherapy. J Labelled Comp Radiopharm. 1997;40:341–3.Google Scholar
  13. 13.
    Koch L, Apostolidis C, Janssens W, Molinet R, Van Geel J. Production of Ac-225 and application of Bi-213 daughter in cancer therapy. Karlsruhe: Institute for Transuranium Elements. European Commission-JRC; 1999.Google Scholar
  14. 14.
    Mirzadeh S. Generator-produced alpha-emitters. Appl Radiat Isot. 1998;49:245–9.Google Scholar
  15. 15.
    Griswold JR, Medvedev DG, Engle JW, Copping R, Fitzsimmons JM, Radchenko V, et al. Large scale accelerator production of 225Ac: effective cross sections for 78-192 MeV protons incident on 232Th targets. Appl Radiat Isot. 2016;118:366–74.  https://doi.org/10.1016/j.apradiso.2016.09.026.PubMedCrossRefGoogle Scholar
  16. 16.
    Weidner JW, Mashnik SG, John KD, Hemez F, Ballard B, Bach H, et al. Proton-induced cross sections relevant to production of 225Ac and 223Ra in natural thorium targets below 200MeV. Appl Radiat Isot. 2012;70(11):2602–7.PubMedCrossRefGoogle Scholar
  17. 17.
    IAEA Technical Meeting Report on “Alpha emitting radionuclides and radiopharmaceuticals for therapy”; Vienna: IAEA Headquarters; 24–28 Jun 2013 (http://www-naweb.iaea.org/napc/iachem/working_materials/TM-44815-report-Alpha-Therapy.pdf and references therein).
  18. 18.
    Griswold JR, Medvedev DG, Engle JW, Copping R, Fitzsimmons JM, Radchenko V, et al. Large scale accelerator production of 225Ac: effective cross sections for 78-192 MeV protons incident on 232Th targets. Appl Radiat Isot. 2016;118:366–74. (and references therein)PubMedCrossRefGoogle Scholar
  19. 19.
    Zalutsky MR, Pruszynski M. Astatine-211: production and availability. Curr Radiopharm. 2011;4(3):177–85.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Kim G, Chun K, Park SH, Kim B. Production of alpha-particle emitting (2)(1)(1)at using 45 MeV alpha-beam. Phys Med Biol. 2014;59(11):2849–60.PubMedCrossRefGoogle Scholar
  21. 21.
    ORNL NIDC site used to provide material through ORNL: https://www.isotopes.gov/catalog/product.php?element=Radium&type=rad&rad_product_index=84 (states monthly up to 740 MBq, 4–6 advance notice)—material is not listed in the current NIDC catalog.
  22. 22.
    Gagnon K, Risler R, Pal S, et al. Design and evaluation of an external high-current target for production of 211At. J Label Compd Radiopharm. 2012;55:436–40.CrossRefGoogle Scholar
  23. 23.
    Makvandi M, Lieberman BP, LeGeyt B, et al. The pre-clinical characterization of an alpha-emitting sigma-2 receptor targeted radiotherapeutic. J Nucl Med Biol. 2016;43:35–41.CrossRefGoogle Scholar
  24. 24.
    Lindergren S, Back T, Jensen HJ. Dry-distillation of astatine-211 from irradiated bismuth targets: a time-saving procedure with high recovery yields. Appl Radiat Isot. 2001;55:157–60.CrossRefGoogle Scholar
  25. 25.
    McDevitt MR, Finn RD, Sgouros G, Ma D, Scheinberg DA. An 225Ac/213Bi generator system for therapeutic clinical applications: construction and operation. Appl Radiat Isot. 1999;50:895–904.PubMedCrossRefGoogle Scholar
  26. 26.
    Larsen RH, Wieland BW, Zalutsky MR. Evaluation of an internal cyclotron target for the production of 211At via the 209Bi (alpha,2n)211 at reaction. Appl Radiat Isot. 1996;47(2):135–43.PubMedCrossRefGoogle Scholar
  27. 27.
    Gagnon KRR, Pal S, Hamlin D, Orzechowski J, Pavan R, Zeisler S, et al. Design and evaluation of an external high-current target for production of 211At. Labelled Comp Radiopharm. 2012;55:436–40.CrossRefGoogle Scholar
  28. 28.
    Martin TM, et al. Preliminary production of 211At at the Texas A & M University cyclotron institute. Health Phys. 2014;107(1):1–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Ogawa K, et al. Preparation and evaluation of an astatine-211-labeled sigma receptor ligand for alpha radionuclide therapy. Nucl Med Biol. 2015;42(11):875–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Nagatsu K, et al. Production of (211)At by a vertical beam irradiation method. Appl Radiat Isot. 2014;94:363–71.PubMedCrossRefGoogle Scholar
  31. 31.
    Lebeda O, Jiran R, Ralis J, Stursa J. A new internal target system for production of (211)At on the cyclotron U-120M. Appl Radiat Isot. 2005;63(1):49–53.PubMedCrossRefGoogle Scholar
  32. 32.
    Makvandi M, et al. The pre-clinical characterization of an alpha-emitting sigma-2 receptor targeted radiotherapeutic. Nucl Med Biol. 2016;43(1):35–41.PubMedCrossRefGoogle Scholar
  33. 33.
    Kim Y-S, Brechbiel MW. An overview of targeted alpha therapy. Tumour Biol. 2012:573–90.Google Scholar
  34. 34.
    Durbin PW. Metabolic characteristics within a chemical family. Health Phys. 1960;2:225–38.PubMedCrossRefGoogle Scholar
  35. 35.
    Ruegg CL, Anderson-Berg WT, Brechbiel MW, Mirzadeh S, Gansow OA, Strand M. Improved in vivo stability and tumor targeting of bismuth-labeled antibody. Cancer Res. 1990;50:4221–6.PubMedGoogle Scholar
  36. 36.
    Taylor DM. The metabolism of actinium in the rat. Health Phys. 1970;19(3):411–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Henriksen G, Bruland OS, Larsen RH. Thorium and actinium polyphosphate compounds as bone-seeking alpha particle-emitting agents. Anticancer Res. 2004;24:101–6.PubMedGoogle Scholar
  38. 38.
    Yuan RR, Wong P, McDevitt MR, Doubrovina E, Leiner I, Bornmann W, et al. Targeted deletion of T-cell clones using alpha-emitting suicide MHC tetramers. Blood. 2004;104:2397–402.PubMedCrossRefGoogle Scholar
  39. 39.
    Sofou S, Thomas JL, Lin HY, McDevitt MR, Scheinberg DA, Sgouros G. Engineered liposomes for potential α-particle therapy of metastatic cancer. J Nucl Med. 2004;45:253–60.PubMedGoogle Scholar
  40. 40.
    Sofou S, Kappel BJ, Jaggi JS, McDevitt MR, Scheinberg DA, Sgouros G. Enhanced retention of the α-particle-emitting daughters of actinium-225 by liposome carriers. Bioconjug Chem. 2007;18:2061–7.PubMedCrossRefGoogle Scholar
  41. 41.
    McDevitt MR, Chattorpadhyay D, Kappel BJ, Jaggi JS, Chiffman SR, Antezak C, et al. Tumor targeting with antibody-functionalized, radiolabeled carbon nanotubes. J Nucl Med. 2007;48:1180–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Chang MY, Seidman J, Sofou S. Enhanced loading efficiency and retention of 225Ac in rigid liposomes for potential targeted therapy of micrometastases. Bioconjug Chem. 2008;19:1274–82.PubMedCrossRefGoogle Scholar
  43. 43.
    Woodward J, Kennel SJ, Stuckey A, Osborne D, Wall J, Rondinone AJ, et al. LaPO4 Nanoparticles doped with actinium-225 that partially sequester daughter radionuclides. Bioconjug Chem. 2011;22:766–76.PubMedCrossRefGoogle Scholar
  44. 44.
    McLaughlin MF, Woodward J, Boll RA, Wall JS, Rondinone AJ, Kennel SJ, et al. Gold coated lanthanide phosphate nanoparticles for targeted alpha generator radiotherapy. PLoS One. 2013;8(1):e54531.  https://doi.org/10.1371/journal.pone.0054531.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Yoshida T, Jin K, Song H, Park S, Huso DL, Zhang Z, et al. Effective treatment of ductal carcinoma in situ with a HER-2-targeted alpha-particle emitting radionuclide in a preclinical model of human breast cancer. Oncotarget. 2016;7(22):33306–15.  https://doi.org/10.18632/oncotarget.8949.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Behling K, Maguire WF, Di Gialleonardo V, Heeb LE, Hassan IF, Veach DR, et al. Remodeling the vascular microenvironment of glioblastoma with α-particles. J Nucl Med. 2016;57(11):1771–7.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Morgenstern A, Bruchertseifer F, Apostolidis C. Targeted alpha therapy with 213Bi. Curr Radiopharm. 2011;4:295–305.PubMedCrossRefGoogle Scholar
  48. 48.
    Huneke RB, Pippin CG, Squire RA, Brechbiel MW, Gansow OA, Strand M. Effective α-particle-mediated radioimmunotherapy of murine leukemia. Cancer Res. 1992;52:5818–20.PubMedGoogle Scholar
  49. 49.
    Behr TM, Behe M, Stabin MG, Wehrmann E, Apostolidis C, Molinet R, et al. High-linear energy transfer (LET) α versus low-LET β emitters in Radioimmunotherapy of solid tumors: therapeutic efficacy and dose-limiting toxicity of 213Bi- versus 90Y-labeled CO17-1A Fab fragments in a human colonic cancer model. Cancer Res. 1999;59:2635–43.PubMedGoogle Scholar
  50. 50.
    McDevitt MR. Barendswaard E, ma D, Lai L, Curcio Mj, Sgouros G, et al. An α-particle emitting antibody ([213Bi]J591) for radioimmunotherapy of prostate cancer. Cancer Res. 2000;60:6095–100.PubMedGoogle Scholar
  51. 51.
    Friesen C, Glatting G, Koop B, Schwarz K, Morgenstern A, Apostolidis C, et al. Breaking chemoresistance and radioresistance with [213Bi]anti-CD45 antibodies in leukemia cells. Cancer Res. 2007;67:1950–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Chan HS, Konijnenberg MW, Daniels T, Nysus M, Makvandi M, de Blois E, et al. Improved safety and efficacy of 213Bi-DOTATATE-targeted alpha therapy of somatostatin receptor-expressing neuroendocrine tumors in mice pre-treated with L-lysine. EJNMMI Res. 2016;6(1):83.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Dorso L, Bigot-Corbel E, Abadie J, Diab M, Gouard S, Bruchertseifer F, et al. Long-term toxicity of 213Bi-labelled BSA in mice. PLoS One. 2016;11(3):e0151330.  https://doi.org/10.1371/journal.pone.0151330.
  54. 54.
    Tan Z, Chen P, Schneider N, Glover S, Cui L, Torgue J, et al. Significant systemic therapeutic effects of high-LET immunoradiation by 212Pb-trastuzumab against prostatic tumors of androgen-independent human prostate cancer in mice. Int J Oncol. 2012;40(6):1881–8.  https://doi.org/10.3892/ijo.2012.1357.PubMedGoogle Scholar
  55. 55.
    Kasten BB, Arend RC, Katre AA, Kim H, Fan J, Ferrone S, et al. B7-H3-targeted 212Pb radioimmunotherapy of ovarian cancer in preclinical models. Nucl Med Biol. 2017;47:23–30.  https://doi.org/10.1016/j.nucmedbio.2017.01.003.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Vaidyanathan G, et al. A kit method for the high level synthesis of [211At]MABG. Bioorg Med Chem. 2007;15(10):3430–6.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Kiess AP, et al. (2S)-2-(3-(1-Carboxy-5-(4-211At-astatobenzamido)pentyl)ureido)-pentanedioic acid for PSMA-targeted alpha-particle radiopharmaceutical therapy. J Nucl Med. 2016;57(10):1569–75.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Zalutsky MR, Reardon DA, Pozzi OR, Vaidyanathan G, Bigner DD. Targeted alpha-particle radiotherapy with 211At-labeled monoclonal antibodies. Nucl Med Biol. 2007;34(7):779–85.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Kaspersen FM, Bos E, Doornmalen AV, Geerlings MW, Apostolidis C, Molinet R. Cytotoxicity of 213Bi- and 225Ac-immunoconjugates. Nucl Med Commun. 1995;16:468–76.PubMedCrossRefGoogle Scholar
  60. 60.
    Kennel SJ, Chappell LL, Dadachova K, Brechbiel MW, Lankford TK, Davis IA, et al. Evaluation of 225Ac for vascular targeted radioimmunotherapy of lung Tumors. Cancer Biother Radiopharm. 2000;15(3):235–44.PubMedCrossRefGoogle Scholar
  61. 61.
    Borchardt PE, Yuan RR, Miederer M, McDevitt MR, Scheinberg DA. Targeted actinium-225 in vivo generators for therapy of ovarian cancer. Cancer Res. 2003;63:5084–90.PubMedGoogle Scholar
  62. 62.
    Song H, Hobbs RF, Vajravelu R, Huso DL, Esaias C, Apostolidis C, et al. Radioimmunotherapy of breast cancer metastases with α-particle emitter 225Ac: comparing efficacy with 213Bi and 90Y. Cancer Res. 2009;69:8941–8.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Jaggi JS, Henke E, Seshan SV, Kappel BJ, Chattopadhyay D, May C, et al. Selective alpha-particle mediated depletion of tumor vasculature with vascular normalization. PLoS One. 2007;2(3):e267.PubMedCentralCrossRefGoogle Scholar
  64. 64.
    Escorcia FE, Henke E, McDevitt MR, Villa CH, Smith-Jones P, Blasberg RG, et al. Selective killing of tumor neovasculature paradoxically improves chemotherapy delivery to Tumors. Cancer Res. 2010;70:9277–86.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Miederer M, McDevitt MR, Sgouros G, Kramer K, Cheung NK, Scheinberg DA. Pharmacokinetics, dosimetry, and toxicity of the targetable atomic generator, 225Ac-HuM195, in nonhuman primates. J Nucl Med. 2004;24:129–37.Google Scholar
  66. 66.
    Miederer M, Henriksen G, Alke A, Mossbrugger I, Quintanilla-Martinez L, Senekowitsch-Schmidtke R, et al. Preclinical evaluation of the α-particle generator nuclide 225Ac for somatostatin receptor radiotherapy of neuroendocrine tumors. Clin Cancer Res. 2008;14:3555–61.PubMedCrossRefGoogle Scholar
  67. 67.
    Norenberg JP, Krenning BJ, Konings IR, Kusewitt DF, Nayak TK, Anderson TL, de Jong M, Garmestani K, Brechbiel MW, Kvols LK. 213Bi-[DOTA0,Tyr3]octreotide peptide receptor radionuclide therapy of pancreatic tumors in a preclinical animal model. Clin Cancer Res 2006; 12:897-903.Google Scholar
  68. 68.
    Drecoll E, Gaertner FC, Miederer M, Blechert B, Vallon M, Müller JM, et al. Treatment of peritoneal carcinomatosis by targeted delivery of the radio-labeled tumor homing peptide 213Bi-DTPA-[F3]2 into the nucleus of tumor cells. PLoS One. 2009;4(5):e5715.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Milenic DE, Brady ED, Garmestani K, Albert PS, Abdulla A, Brechbiel MW. Improved efficacy of α-particle-targeted radiation therapy. Cancer. 2010:1059–66.Google Scholar
  70. 70.
    Bethge WA, Wilbur DS, Storb R, Hamlin DK, Santos EB, Brechbiel MW, et al. Radioimmunotherpay with bismuth-213 as conditioning for nonmyeloablative allogenic hematopoietic cell transplantation in dogs: a dose deescalation study. Transplantation. 2004;78:352–9.PubMedCrossRefGoogle Scholar
  71. 71.
    Milenic DE, Garmestani K, Brady ED, Albert PS, Ma D, Abdulla A, et al. Alpha-particle radioimmunotherapy of disseminated peritoneal disease using a (212)Pb-labeled radioimmunoconjugate targeting HER2. Cancer Biother Radiopharm. 2005;20(5):557–68.PubMedCrossRefGoogle Scholar
  72. 72.
    Miao Y, Hylarides M, Fisher DR, Shelton T, Moore H, Wester DW, et al. Melanoma therapy via peptide-targeted {alpha}-radiation. Clin Cancer Res. 2005;11(15):5616–21.PubMedCrossRefGoogle Scholar
  73. 73.
    Green DJ, Shadman M, Jones JC, Frayo SL, Kenoyer AL, Hylarides MD, et al. Astatine-211 conjugated to an anti-CD20 monoclonal antibody eradicates disseminated B-cell lymphoma in a mouse model. Blood. 2015;125(13):2111–9.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Jaggi JS, Seshan SV, McDevitt MR, LaPerle K, Sgourous G, Scheinberg DA. Renal tubulointerstitial changes after internal irradiation with α-particle-emitting actinium daughters. J Am Soc Nephrol. 2005;16:2677–89.PubMedCrossRefGoogle Scholar
  75. 75.
    Jaggi JS, Seshan SV, McDevitt MR, Sgouros G, Hyjek E, Scheinberg DA. Mitigation of radiation nephropathy after internal α-particle irradiation of the kidneys. Int J Radiat Oncol Biol Phys. 2006;64:1503–12.PubMedCrossRefGoogle Scholar
  76. 76.
    Jaggi JS, Kappel BJ, McDevitt MR, Sgouros G, Flombaum CD, Cabassa C, et al. Efforts to control the errant products of a targeted in vivo generator. Cancer Res. 2005;65:4888–95.PubMedCrossRefGoogle Scholar
  77. 77.
    Song EY, Rizvi SMA, Qu CF, Raja C, Brechbiel MW, Morgenstern A, et al. Pharmacokinetics and toxicity of 213Bi-labeled PAI2 in preclinical targeted alpha therapy for cancer. Cancer Biol Ther. 2007;6(6):898–904.PubMedCrossRefGoogle Scholar
  78. 78.
    Chan HS, Konijnenberg MW, Daniels T, Nysus M, Makvandi M, de Blois E, et al. Improved safety and efficacy of 213Bi-DOTATATE-targeted alpha therapy of somatostatin receptor-expressing neuroendocrine tumors in mice pre-treated with L-lysine. Eur J Nucl Med Mol Imaging Res. 2016;6(1):83.Google Scholar
  79. 79.
    Jaggi JS, Carrasquillo JA, Seshan SV, Zanzonico P, Henke E, Nagel A, et al. Improved tumor imaging and therapy via i.v. IgG-mediated time-sequential modulation of neonatal Fc receptor. J Clin Invest. 2007;117:2422–30.PubMedCrossRefGoogle Scholar
  80. 80.
    Chatal JF, Davodeau F, Cherel M, Barbet J. Different ways to improve the clinical effectiveness of radioimmunotherapy in solid tumors. J Cancer Res Ther. 2009;5:S36–40.PubMedCrossRefGoogle Scholar
  81. 81.
    Prise KM, Schettino G, Folkard M, Held KD. New insights on cell death from radiation exposure. Lancet Oncol. 2005;6:520–8.PubMedCrossRefGoogle Scholar
  82. 82.
    Brady D, O’Sullivan JM, Prise KM. What is the role of bystander response in radionuclide therapies. Front Oncol. 2013;3:1–5.CrossRefGoogle Scholar
  83. 83.
    Marin A, Martin M, Lina O, Alvarenga F, Lopez M. Fernandez, et al. Bystander effects and radiotherapy. Rep Pract Oncol Radiother. 2015;20:12–21.PubMedCrossRefGoogle Scholar
  84. 84.
    Jurcic JG, Rosenblat TL. Targeted alpha-particle immunotherapy for acute myeloid leukemia. Am Soc Clin Oncol Educ Book. 2014:e126–31. doi:  https://doi.org/10.14694/EdBook_AM.2014.34.e126.
  85. 85.
    Jurcic JG, Ravandi F, Pagel JM, Park JH, Douglas Smith B, Douer D, Yair Levy M, Estey E , Kantarjian HM, Earle D, Cicic D, Scheinberg DA. Phase I trial of α-particle therapy with actinium-225 (225Ac)-lintuzumab (anti-CD33) and low-dose cytarabine (LDAC) in older patients with untreated acute myeloid leukemia (AML.) J Clin Oncol 33, 2015 (suppl; abstr 7050).Google Scholar
  86. 86.
    Kratochwil C, Bruchertseifer F, Giesel FL, Weis M, Verburg FA, Mottaghy F, et al. 225Ac-PSMA-617 for PSMA-targeted α-radiation therapy of metastatic castration-resistant prostate cancer. J Nucl Med. 2016;57(12):1941–4.PubMedCrossRefGoogle Scholar
  87. 87.
    Zalutsky MR, Reardon DA, Akabani G, Coleman RE, Friedman AH, Friedman HS, et al. Clinical experience with alpha-particle emitting 211At: treatment of recurrent brain tumor patients with 211At-labeled chimeric antitenascin monoclonal antibody 81C6. J Nucl Med. 2008;49(1):30–8.PubMedCrossRefGoogle Scholar
  88. 88.
    Andersson H, Cederkrantz E, Bäck T, Divgi C, Elgqvist J, Himmelman J, et al. Intraperitoneal alpha-particle radioimmunotherapy of ovarian cancer patients: pharmacokinetics and dosimetry of (211)at-MX35 F(ab')2—a phase I study. J Nucl Med. 2009;50(7):1153–60.  https://doi.org/10.2967/jnumed.109.062604.PubMedCrossRefGoogle Scholar
  89. 89.
    Cederkrantz E, Andersson H, Bernhardt P, Bäck T, Hultborn R, Jacobsson L, et al. Absorbed doses and risk estimates of (211)At-MX35 F(ab')2 in intraperitoneal therapy of ovarian cancer patients. Int J Radiat Oncol Biol Phys. 2015;93(3):569–76.PubMedCrossRefGoogle Scholar
  90. 90.
    Jurcic JG, Larson SM, Sgouros G, McDevitt MR, Finn RD, Divgi CR, et al. Targeted alpha particle immunotherapy for myeloid leukemia. Blood. 2002;100(4):1233–9.PubMedGoogle Scholar
  91. 91.
    Rosenblat TL, McDevitt MR, Mulford DA, Pandit-Taskar N, Divgi CR, Panageas KS, et al. Sequential cytarabine and alpha-particle immunotherapy with bismuth-213-lintuzumab (HuM195) for acute myeloid leukemia. Clin Cancer Res. 2010;16(21):5303–11.  https://doi.org/10.1158/1078-0432.CCR-10-0382.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Raja C, Graham P, Abbas Rizvi SM, Song E, Goldsmith H, Thompson J, et al. Interim analysis of toxicity and response in phase 1 trial of systemic targeted alpha therapy for metastatic melanoma. Cancer Biol Ther. 2007;6(6):846–52.PubMedCrossRefGoogle Scholar
  93. 93.
    Sathekge M, Knoesen O, Meckel M, Modiselle M, Vorster M, Marx S. 213Bi-PSMA-617 targeted alpha-radionuclide therapy in metastatic castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2017;44(6):1099–100.  https://doi.org/10.1007/s00259-017-3657-9.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Allen BJ, Singla AA, Rizvi SM, Graham P, Bruchertseifer F, Apostolidis C, et al. Analysis of patient survival in a phase I trial of systemic targeted α-therapy for metastatic melanoma. Immunotherapy. 2011;3(9):1041–50.  https://doi.org/10.2217/imt.11.97.PubMedCrossRefGoogle Scholar
  95. 95.
    Allen BJ, Raja C, Rizvi S, Li Y, Tsui W, Graham P, et al. Intralesional targeted alpha therapy for metastatic melanoma. Cancer Biol Ther. 2005;4(12):1318–24.PubMedCrossRefGoogle Scholar
  96. 96.
    Cordier D, Forrer F, Bruchertseifer F, Morgenstern A, Apostolidis C, Good S, et al. Targeted alpha-radionuclide therapy of functionally critically located gliomas with 213Bi-DOTA-[Thi8,met(O2)11]-substance P: a pilot trial. Eur J Nucl Med Mol Imaging. 2010;37(7):1335–44.  https://doi.org/10.1007/s00259-010-1385-5.PubMedCrossRefGoogle Scholar
  97. 97.
    Kratochwil C, Giesel FL, Bruchertseifer F, Mier W, Apostolidis C, Boll R, et al. 213Bi-DOTATOC 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(11):2106–19.  https://doi.org/10.1007/s00259-014-2857-9.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Meredith RF, Torgue JJ, Rozgaja TA, Banaga EP, Bunch PW, Alvarez RD, et al. Safety and outcome measures of first-in-human intraperitoneal α radioimmunotherapy with 212Pb-TCMC-Trastuzumab. Am J Clin Oncol. 2016.  https://doi.org/10.1097/COC.0000000000000353
  99. 99.
    Nilsson S, Larsen RH, Fossa SD, et al. First clinical experience with alpha-emitting radium-223 in the treatment of skeletal metastases. Clin Cancer Res. 2005;11(12):4451–9.PubMedCrossRefGoogle Scholar
  100. 100.
    Nilsson S, Strang P, Aksnes AK, Franzèn L, Olivier P, Pecking A, et al. A randomized, dose-response, multicenter phase II study of radium-223 chloride for the palliation of painful bone metastases in patients with castration-resistant prostate cancer. Eur J Cancer. 2012;48(5):678–86.  https://doi.org/10.1016/j.ejca.2011.12.023.PubMedCrossRefGoogle Scholar
  101. 101.
    Nilsson S, Cislo P, Sartor O, Vogelzang NJ, Coleman RE, O’Sullivan JM, et al. Patient-reported quality-of-life analysis of radium-223 dichloride from the phase III ALSYMPCA study. Ann Oncol. 2016;27(5):868–74.  https://doi.org/10.1093/annonc/mdw065.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Kluetz PG, Pierce W, Maher VE, Zhang H, Tang S, Song P, et al. Radium Ra 223 dichloride injection: U.S. Food and Drug Administration drug approval summary. Clin Cancer Res. 2014;20(1):9–14.  https://doi.org/10.1158/1078-0432.CCR-13-2665.PubMedCrossRefGoogle Scholar
  103. 103.
    Hamcher KA, Sgouros G. A schema for estimating absorbed dose to organs following the administration of radionuclides with multiple unstable daughters: a matrix approach. Med Phys. 1999;26(12):2526–8.CrossRefGoogle Scholar
  104. 104.
    Hamcher KA, Den RB, Den EI, et al. Cellular dose conversion factors for α-particle-emitting radionuclides of interest in radionuclide therapy. J Nucl Med. 2001;42:1216–21.Google Scholar
  105. 105.
    Hamacher KA, Sgouros G. Theoretical estimation of absorbed dose to organs in radioimmunotherapy using radionuclides with multiple unstable daughters. Med Phys. 2001;28(9):1857–74.PubMedCrossRefGoogle Scholar
  106. 106.
    Sgouros G, Roeske JC, McDevitt MR, Palm S, Allen BJ, Fisher DR, et al. MIRD pamphlet no. 22 (abridged): radiobiology and Dosimetry of α-particle emitters for targeted radionuclide therapy. J Nucl Med. 2010;51(2):311–28.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Coleman R. Treatment of metastatic bone disease and the emerging role of radium-223. Semin Nucl Med. 2016;46(2):99–104.  https://doi.org/10.1053/j.semnuclmed.2015.10.012.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Mehran Makvandi
    • 1
  • Edouard Dupis
    • 2
  • Jonathan W. Engle
    • 3
  • F. Meiring Nortier
    • 3
  • Michael E. Fassbender
    • 3
  • Sam Simon
    • 1
  • Eva R. Birnbaum
    • 3
  • Robert W. Atcher
    • 1
    • 3
  • Kevin D. John
    • 3
  • Olivier Rixe
    • 2
  • Jeffrey P. Norenberg
    • 1
  1. 1.Radiopharmaceutical Sciences Program, College of Pharmacy, Health Sciences CenterUniversity of New MexicoAlbuquerqueUSA
  2. 2.Experimental Therapeutics UnitUniversity of New Mexico Comprehensive Cancer CenterAlbuquerqueUSA
  3. 3.Los Alamos National LaboratoryLos AlamosUSA

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