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Radiopharmaceutical therapy in cancer: clinical advances and challenges

Nature Reviews Drug Discovery volume 19, pages 589–608 (2020)Cite this article

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An Author Correction to this article was published on 07 September 2020

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Abstract

Radiopharmaceutical therapy (RPT) is emerging as a safe and effective targeted approach to treating many types of cancer. In RPT, radiation is systemically or locally delivered using pharmaceuticals that either bind preferentially to cancer cells or accumulate by physiological mechanisms. Almost all radionuclides used in RPT emit photons that can be imaged, enabling non-invasive visualization of the biodistribution of the therapeutic agent. Compared with almost all other systemic cancer treatment options, RPT has shown efficacy with minimal toxicity. With the recent FDA approval of several RPT agents, the remarkable potential of this treatment is now being recognized. This Review covers the fundamental properties, clinical development and associated challenges of RPT.

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Fig. 1: Tumour cell irradiation: radiotherapy versus radiopharmaceutical therapy.
Fig. 2: Publications per year related to RPT.
Fig. 3: Basic RPT constructs used for radiation delivery.
Fig. 4: PSMA and folate receptor RPT.
Fig. 5: Mechanism of action of peptide receptor radionuclide therapy.
Fig. 6: Target antigens that have been used in antibody-based radiopharmaceutical therapy.

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References

  1. Wong, C. H., Siah, K. W. & Lo, A. W. Estimation of clinical trial success rates and related parameters. Biostatistics 20, 273–286 (2018).

    PubMed Central  Google Scholar 

  2. Lin, A. et al. Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Sci. Transl Med. 11, eaaw8412 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Gill, M. R., Falzone, N., Du, Y. & Vallis, K. A. Targeted radionuclide therapy in combined-modality regimens. Lancet Oncol. 18, e414–e423 (2017).

    CAS  PubMed  Google Scholar 

  4. Dolgin, E. Radioactive drugs emerge from the shadows to storm the market. Nat. Biotechnol. 36, 1125–1127 (2018).

    CAS  PubMed  Google Scholar 

  5. Knut, L. Radiosynovectomy in the therapeutic management of arthritis. World J. Nucl. Med. 14, 10–15 (2015).

    PubMed  PubMed Central  Google Scholar 

  6. Kresnik, E. In: Local Treatment of Inflammatory Joint Diseases: Benefits and Risks (eds Kampen, W. U., & Fischer, M.) 81–93 (Springer International Publishing, 2015).

  7. Bentzen, S. M. et al. Quantitative analyses of normal tissue effects in the clinic (QUANTEC): an introduction to the scientific issues. Int. J. Radiat. Oncol. Biol. Phys. 76, S3–S9 (2010). Summary of radiation dose versus response data from radiotherapy experience.

    PubMed  PubMed Central  Google Scholar 

  8. Dale, R. & Carabe-Fernandez, A. The radiobiology of conventional radiotherapy and its application to radionuclide therapy. Cancer Biother. Radiopharm. 20, 47–51 (2005).

    CAS  PubMed  Google Scholar 

  9. Amro, H., Wilderman, S. J., Dewaraja, Y. K. & Roberson, P. L. Methodology to incorporate biologically effective dose and equivalent uniform dose in patient-specific 3-dimensional dosimetry for non-Hodgkin lymphoma patients targeted with 131I-tositumomab therapy. J. Nucl. Med. 51, 654–659 (2010).

    CAS  PubMed  Google Scholar 

  10. Fowler, J. F. Radiobiological aspects of low-dose rates in radioimmunotherapy. Int. J. Radiat. Oncol. Biol. Phys. 18, 1261–1269 (1990). Radiobiological treatment of RPT.

    CAS  PubMed  Google Scholar 

  11. McDevitt, M. R. et al. Radioimmunotherapy with alpha-emitting nuclides. Eur. J. Nucl. Med. 25, 1341–1351 (1998).

    CAS  PubMed  Google Scholar 

  12. Wessels, B. W. & Rogus, R. D. Radionuclide selection and model absorbed dose calculations for radiolabeled tumor associated antibodies. Med. Phys. 11, 638–645 (1984).

    CAS  PubMed  Google Scholar 

  13. Bloomer, W. D., McLaughlin, W. H., Adelstein, S. J. & Wolf, A. P. Therapeutic applications of Auger and alpha emitting radionuclides. Strahlentherapie 160, 755–757 (1984).

    CAS  PubMed  Google Scholar 

  14. O’Donoghue, J. A., Bardies, M. & Wheldon, T. E. Relationships between tumor size and curability for uniformly targeted therapy with beta-emitting radionuclides. J. Nucl. Med. 36, 1902–1909 (1995). Demonstrates that, in contrast to external-beam radiotherapy, in RPT fewer cells do not lead to greater tumour control probability.

    CAS  PubMed  Google Scholar 

  15. Cherry, S. R., Sorenson, J. A., & Phelps, M. E. Physics in Nuclear Medicine e-Book (Elsevier Health Sciences, 2012).

  16. Behr, T. M. et al. Therapeutic advantages of Auger electron- over beta-emitting radiometals or radioiodine when conjugated to internalizing antibodies. Eur. J. Nucl. Med. 27, 753–765 (2000).

    CAS  PubMed  Google Scholar 

  17. Bodei, L., Kassis, A. I., Adelstein, S. J. & Mariani, G. Radionuclide therapy with iodine-125 and other Auger-electron-emitting radionuclides: experimental models and clinical applications. Cancer Biother. Radiopharm. 18, 861–877 (2003).

    CAS  PubMed  Google Scholar 

  18. Howell, R. W. et al. in Biophysical Aspects of Auger Processes (Howell, R. W., Narra, V. R., Sastry, K. S. R. & Rao, D. V. Eds). 290–318 (Medical Physics, 1991).

  19. Kassis, A. I., Adelstein, S. J. & Mariani, G. Radiolabeled nucleoside analogs in cancer diagnosis and therapy. Q. J. Nucl. Med. 40, 301–319 (1996).

    CAS  PubMed  Google Scholar 

  20. Kiess, A. P. et al. Auger radiopharmaceutical therapy targeting prostate-specific membrane antigen. J. Nucl. Med. 56, 1401–1407 (2015).

    CAS  PubMed  Google Scholar 

  21. Macapinlac, H. A. et al. Pilot clinical trial of 5-[125I]iodo-2’-deoxyuridine in the treatment of colorectal cancer metastatic to the liver. J. Nucl. Med. 37 (Suppl. 4), 25–29 (1996).

    Google Scholar 

  22. Daghighian, F. et al. Pharmacokinetics and dosimetry of iodine-125-IUdR in the treatment of colorectal cancer metastatic to liver. J. Nucl. Med. 37 (Suppl. 4), 29–32 (1996).

    Google Scholar 

  23. Sgouros, G. et al. Mathematical model of 5-[125I]iodo-2’-deoxyuridine treatment: continuous infusion regimens for hepatic metastases. Int. J. Radiat. Oncol. Biol. Phys. 41, 1177–1183 (1998).

    CAS  PubMed  Google Scholar 

  24. Rebischung, C. et al. First human treatment of resistant neoplastic meningitis by intrathecal administration of MTX plus 125IUdR. Int. J. Radiat. Biol. 84, 1123–1129 (2008).

    CAS  PubMed  Google Scholar 

  25. Behr, T. M. et al. 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. 76, 738–748 (1998).

    CAS  PubMed  Google Scholar 

  26. Ku, A., Facca, V. J., Cai, Z. & Reilly, R. M. Auger electrons for cancer therapy - a review. EJNMMI Radiopharm. Chem. 4, 27 (2019).

    PubMed  PubMed Central  Google Scholar 

  27. Brooks, R. C. et al. Metal complexes of bleomycin: evaluation of [Rh-105]-bleomycin for use in targeted radiotherapy. Nucl. Med. Biol. 26, 421–430 (1999).

    CAS  PubMed  Google Scholar 

  28. Miao, Y., Owen, N. K., Fisher, D. R., Hoffman, T. J. & Quinn, T. P. Therapeutic efficacy of a 188Re-labeled alpha-melanocyte-stimulating hormone peptide analog in murine and human melanoma-bearing mouse models. J. Nucl. Med. 46, 121–129 (2005).

    CAS  PubMed  Google Scholar 

  29. Champion, C., Quinto, M. A., Morgat, C., Zanotti-Fregonara, P. & Hindié, E. Comparison between three promising ß-emitting radionuclides, 67Cu, 47Sc and 161Tb, with emphasis on doses delivered to minimal residual disease. Theranostics 6, 1611–1618 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Howell, R. W., Goddu, S. M. & Rao, D. V. Application of the linear-quadratic model to radioimmunotherapy: further support for the advantage of longer-lived radionuclides. J. Nucl. Med. 35, 1861–1869 (1994).

    CAS  PubMed  Google Scholar 

  31. Watson, E. E., Stabin, M. G., Davis, J. L. & Eckerman, K. F. A model of the peritoneal cavity for use in internal dosimetry. J. Nucl. Med. 30, 2002–2011 (1989).

    CAS  PubMed  Google Scholar 

  32. Zimmermann, R. G. Why are investors not interested in my radiotracer? The industrial and regulatory constraints in the development of radiopharmaceuticals. Nucl. Med. Biol. 40, 155–166 (2013).

    CAS  PubMed  Google Scholar 

  33. Mikheev, N. B. Radioactive colloidal solutions and suspensions for medical use. At. Energy Rev. 14, 3–36 (1976).

    CAS  PubMed  Google Scholar 

  34. Bayly, R. J., Peacegood, J. A. & Peake, S. C. 90Y ferric hydroxide colloid. Ann. Rheum. Dis. 32 (Suppl.), 10 (1973).

    PubMed Central  Google Scholar 

  35. Washburn, L. C. et al. 90Y-labeled monoclonal antibodies for cancer therapy. Int. J. Radiat. Appl. Instrum. Part B Nucl. Med. Biol. 13, 453–456 (1986).

    CAS  Google Scholar 

  36. Kozak, R. W. et al. Nature of the bifunctional chelating agent used for radioimmunotherapy with yttrium-90 monoclonal antibodies: critical factors in determining in vivo survival and organ toxicity. Cancer Res. 49, 2639–2644 (1989).

    CAS  PubMed  Google Scholar 

  37. Brechbiel, M. W. & Gansow, O. A. Backbone-substituted DTPA ligands for 90Y radioimmunotherapy. Bioconjug. Chem. 2, 187–194 (1991). Introduces a novel DTPA chelate for radioimmunotherapy with metallic radionuclides.

    CAS  PubMed  Google Scholar 

  38. Stewart, J. S. et al. Intraperitoneal radioimmunotherapy for ovarian cancer: pharmacokinetics, toxicity, and efficacy of I-131 labeled monoclonal antibodies. Int. J. Radiat. Oncol. Biol. Phys. 16, 405–413 (1989).

    CAS  PubMed  Google Scholar 

  39. Oei, A. L. et al. Decreased intraperitoneal disease recurrence in epithelial ovarian cancer patients receiving intraperitoneal consolidation treatment with yttrium-90-labeled murine HMFG1 without improvement in overall survival. Int. J. Cancer 120, 2710–2714 (2007).

    CAS  PubMed  Google Scholar 

  40. Waldmann, T. A. et al. Radioimmunotherapy of interleukin-2R alpha-expressing adult T-cell leukemia with yttrium-90-labeled anti-Tac. Blood 86, 4063–4075 (1995).

    CAS  PubMed  Google Scholar 

  41. Foss, F. M. et al. Phase I study of the pharmacokinetics of a radioimmunoconjugate, 90Y-T101, in patients with CD5-expressing leukemia and lymphoma. Clin. Cancer Res. 4, 2691–2700 (1998).

    CAS  PubMed  Google Scholar 

  42. Witzig, T. E. et al. Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20+ B-cell non-Hodgkin’s lymphoma. J. Clin. Oncol. 17, 3793–3803 (1999).

    CAS  PubMed  Google Scholar 

  43. Nisa, L., Savelli, G. & Giubbini, R. Yttrium-90 DOTATOC therapy in GEP-NET and other SST2 expressing tumors: a selected review. Ann. Nucl. Med. 25, 75–85 (2011).

    CAS  PubMed  Google Scholar 

  44. Salem, R. & Thurston, K. G. Radioembolization with 90yttrium microspheres: a state-of-the-art brachytherapy treatment for primary and secondary liver malignancies. Part 1: technical and methodologic considerations. J. Vasc. Interv. Radiol. 17, 1251–1278 (2006).

    PubMed  Google Scholar 

  45. Lau, W. Y. et al. Selective internal radiation therapy for nonresectable hepatocellular carcinoma with intraarterial infusion of 90yttrium microspheres. Int. J. Radiat. Oncol. Biol. Phys. 40, 583–592 (1998). Early report of microsphere therapy for hepatic artery infusion.

    CAS  PubMed  Google Scholar 

  46. Popperl, G. et al. Selective internal radiation therapy with SIR-Spheres in patients with nonresectable liver tumors. Cancer Biother. Radiopharm. 20, 200–208 (2005).

    PubMed  Google Scholar 

  47. Mancini, R. et al. A multicentric phase II clinical trial on intra-arterial hepatic radiotherapy with 90yttrium SIR-spheres in unresectable, colorectal liver metastases refractory to i.v. chemotherapy: preliminary results on toxicity and response rates. In Vivo 20, 711–714 (2006).

    CAS  PubMed  Google Scholar 

  48. Maleux, G. et al. Yttrium-90 radioembolization for the treatment of chemorefractory colorectal liver metastases: technical results, clinical outcome and factors potentially influencing survival. Acta Oncol. 55, 486–495 (2016).

    CAS  PubMed  Google Scholar 

  49. Yue, J. et al. Comparison of quantitative Y-90 SPECT and non-time-of-flight PET imaging in post-therapy radioembolization of liver cancer. Med. Phys. 43, 5779 (2016).

    PubMed  PubMed Central  Google Scholar 

  50. Das, T. & Banerjee, S. Theranostic applications of lutetium-177 in radionuclide therapy. Curr. Radiopharm. 9, 94–101 (2016).

    CAS  PubMed  Google Scholar 

  51. Tarasov, V. A., Andreev, O. I., Romanov, E. G., Kuznetsov, R. A., Kupriyanov, V. V. & Tselishchev, I. V. Production of no-carrier added lutetium-177 by irradiation of enriched ytterbium-176. Curr. Radiopharm. 8, 95–106 (2015).

    CAS  PubMed  Google Scholar 

  52. Banerjee, S., Pillai, M. R. A. & Knapp, F. F. Lutetium-177 therapeutic radiopharmaceuticals: linking chemistry, radiochemistry, and practical applications. Chem. Rev. 115, 2934–2974 (2015).

    CAS  PubMed  Google Scholar 

  53. Sgouros, G. et al. MIRD Monograph: Radiobiology and Dosimetry for Radiopahrmaceutical Therapy with Alpha-Particle Emitters (ed. Sgouros, G.). (SNMMI, 2015). Comprehensive review of radiobiology and dosimetry for α-emitter RPT.

  54. Sgouros, G. et al. MIRD pamphlet no. 22 (abridged): radiobiology and dosimetry of alpha-particle emitters for targeted radionuclide therapy. J. Nucl. Med. 51, 311–328 (2010).

    CAS  PubMed  Google Scholar 

  55. Parker, C. et al. Targeted alpha therapy, an emerging class of cancer agents a review. JAMA Oncol. 4, 1765–1772 (2018).

    PubMed  Google Scholar 

  56. Parker, C. et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N. Engl. J. Med. 369, 213–223 (2013). ASYMPCA trial report that led to approval of radium-223 for treatment of patients with prostate cancer with bone metastases.

    CAS  PubMed  Google Scholar 

  57. Kratochwil, C. et al. 225Ac-PSMA-617 for PSMA-targeted α-radiation therapy of metastatic castration-resistant prostate cancer. J. Nucl. Med. 57, 1941–1944 (2016). Striking imaging-based demonstration of the remarkable response that may be obtained with α-emitter RPT.

    CAS  PubMed  Google Scholar 

  58. Kratochwil, C., Haberkorn, U. & Giesel, F. L. Radionuclide therapy of metastatic prostate cancer. Semin. Nucl. Med. 49, 313–325 (2019).

    PubMed  Google Scholar 

  59. Parker, C., Heidenreich, A., Nilsson, S. & Shore, N. Current approaches to incorporation of radium-223 in clinical practice. Prostate Cancer Prostatic Dis. 21, 37–47 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Subbiah, V. et al. Alpha particle radium 223 dichloride in high-risk osteosarcoma: a phase I dose escalation trial. Clin. Cancer Res. 25, 3802–3810 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Geva, R. et al. Radium-223 in combination with paclitaxel in cancer patients with bone metastases: safety results from an open-label, multicenter phase Ib study. Eur. J. Nucl. Med. Mol. Imaging 46, 1092–1101 (2019).

    CAS  PubMed  Google Scholar 

  62. Takalkar, A., Paryani, B., Adams, S. & Subbiah, V. Radium-223 dichloride therapy in breast cancer with osseous metastases. BMJ Case Rep. 2015, bcr2015211152 (2015).

    PubMed  PubMed Central  Google Scholar 

  63. Eckerman, K. F. & Enzo, A. MIRD: Radionuclide Data and Decay Schemes, 2nd edn. (Society of Nuclear Medicine, 2008).

  64. Hellman, S., Devita V. T. and Rosenberg, S. A. Cancer: Principles & Practice of Oncology. 265–288 (Lippincott Williams & Wilkins, 2001).

  65. Longcor, J. & Oliver, K. Phase 1, open-label, dose escalation study of I-131-CLR1404 (CLR 131) in patients with relapsed or refractory multiple myeloma. Blood 134, 1864 (2019).

    Google Scholar 

  66. Ciernik, I. F. et al. Proton-based radiotherapy for unresectable or incompletely resected osteosarcoma. Cancer 117, 4522–4530 (2011).

    PubMed  Google Scholar 

  67. Oertel, S. et al. Radiotherapy in the treatment of primary osteosarcoma-a single center experience. Tumori 96, 582–588 (2010).

    PubMed  Google Scholar 

  68. Senthamizhchelvan, S. et al. Tumor dosimetry and response for 153Sm-ethylenediamine tetramethylene phosphonic acid therapy of high-risk osteosarcoma. J. Nucl. Med. 53, 215–224 (2012).

    CAS  PubMed  Google Scholar 

  69. Hobbs, R. F. et al. A treatment planning method for sequentially combining radiopharmaceutical therapy and external radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 80, 1256–1262 (2011).

    PubMed  Google Scholar 

  70. Wessels, B. W. et al. MIRD pamphlet no. 20: the effect of model assumptions on kidney dosimetry and response-implications for radionuclide therapy. J. Nucl. Med. 49, 1884–1899 (2008).

    PubMed  Google Scholar 

  71. Kiess, A. P. 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. 57, 1569–1575 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Jentzen, W. et al. Pre-therapeutic I-124 PET(/CT) dosimetry confirms low average absorbed doses per administered I-131 activity to the salivary glands in radioiodine therapy of differentiated thyroid cancer. Eur. J. Nucl. Med. Mol. Imaging 37, 884–895 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Hobbs, R. F., Jentzen, W., Bockisch, A. & Sgouros, G. Monte Carlo-based 3-dimensional dosimetry of salivary glands in radioiodine treatment of differentiated thyroid cancer estimated using 124I PET. Q. J. Nucl. Med. Mol. Imaging 57, 79–91 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Hobbs, R. F. et al. A bone marrow toxicity model for 223Ra alpha-emitter radiopharmaceutical therapy. Phys. Med. Biol. 57, 3207–3222 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Back, T. & Jacobsson, L. The alpha-camera: a quantitative digital autoradiography technique using a charge-coupled device for ex vivo high-resolution bioimaging of alpha-particles. J. Nucl. Med. 51, 1616–1623 (2010). α-Camera imaging technique to assess distribution of α-particles in tissues.

    PubMed  Google Scholar 

  76. Miller, B. W. et al. Quantitative single-particle digital autoradiography with alpha-particle emitters for targeted radionuclide therapy using the iQID camera. Med. Phys. 42, 4094–4105 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Miller, B. W. Radiation imagers for quantitative, single-particle digital autoradiography of alpha- and beta-particle emitters. Semin. Nucl. Med. 48, 367–376 (2018).

    PubMed  Google Scholar 

  78. Ljungberg, M. & Gleisner, K. S. 3-D image-based dosimetry in radionuclide therapy. IEEE Trans. Radiat. Plasma Med. Sci. 2, 527–540 (2018).

    Google Scholar 

  79. Sgouros, G. & Hobbs, R. F. Dosimetry for radiopharmaceutical therapy. Semin. Nucl. Med. 44, 172–178 (2014).

    PubMed  PubMed Central  Google Scholar 

  80. Dewaraja, Y. K., Ljungberg, M., Green, A. J., Zanzonico, P. B. & Frey, E. C. MIRD pamphlet no. 24: guidelines for quantitative 131I SPECT in dosimetry applications. J. Nucl. Med. 54, 122390 (2013).

    Google Scholar 

  81. Bolch, W. E., Eckerman, K. F., Sgouros, G. & Thomas, S. R. MIRD pamphlet no. 21: a generalized schema for radiopharmaceutical dosimetry-standardization of nomenclature. J. Nucl. Med. 50, 477–484 (2009). Mathematical formalism for radiopharmaceutical dosimetry.

    CAS  PubMed  Google Scholar 

  82. Vaziri, B., Wu, H., Dhawan, A. P., Du, P. & Howell, R. W. MIRD pamphlet no. 25: MIRDcell V2.0 software tool for dosimetric analysis of biologic response of multicellular populations. J. Nucl. Med. 55, 1557–1564 (2014).

    PubMed  Google Scholar 

  83. Dewaraja, Y. K. et al. MIRD pamphlet no. 23: quantitative SPECT for patient-specific 3-dimensional dosimetry in internal radionuclide therapy. J. Nucl. Med. 53, 1310–1325 (2012).

    CAS  PubMed  Google Scholar 

  84. Bolch, W. E. et al. MIRD pamphlet no. 17: the dosimetry of nonuniform activity distributions-radionuclide S values at the voxel level. Medical Internal Radiation Dose Committee. J. Nucl. Med. 40, 11S–36S (1999).

    CAS  PubMed  Google Scholar 

  85. Furhang, E. E., Chui, C. S., Kolbert, K. S., Larson, S. M. & Sgouros, G. Implementation of a Monte Carlo dosimetry method for patient-specific internal emitter therapy. Med. Phys. 24, 1163–1172 (1997).

    CAS  PubMed  Google Scholar 

  86. Kolbert, K. S. et al. Implementation and evaluation of patient-specific three-dimensional internal dosimetry. J. Nucl. Med. 38, 301–308 (1997).

    CAS  PubMed  Google Scholar 

  87. Cremonesi, M. et al. Correlation of dose with toxicity and tumour response to Y-90- and Lu-177-PRRT provides the basis for optimization through individualized treatment planning. Eur. J. Nucl. Med. Mol. Imaging 45, 2426–2441 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Pacilio, M. et al. A case report of image-based dosimetry of bone metastases with Alpharadin (Ra-223-dichloride) therapy: inter-fraction variability of absorbed dose and follow-up. Ann. Nucl. Med. 30, 163–168 (2016).

    PubMed  Google Scholar 

  89. Stokke, C. et al. Dosimetry-based treatment planning for molecular radiotherapy: a summary of the 2017 report from the Internal Dosimetry Task Force. EJNMMI Phys. 4, 27 (2017).

    PubMed  PubMed Central  Google Scholar 

  90. Dewaraja, Y. K. et al. Tumor-absorbed dose predicts progression-free survival following 131I-tositumomab radioimmunotherapy. J. Nucl. Med. 55, 1047–1053 (2014).

    CAS  PubMed  Google Scholar 

  91. O’Donoghue, J. A. et al. Hematologic toxicity in radioimmunotherapy: dose-response relationships for I-131 labeled antibody therapy. Cancer Biother. Radiopharm. 17, 435–443 (2002).

    CAS  PubMed  Google Scholar 

  92. Sgouros, G. & Goldenberg, D. M. Radiopharmaceutical therapy in the era of precision medicine. Eur. J. Cancer 50, 2360–2363 (2014).

    PubMed  PubMed Central  Google Scholar 

  93. Hertz, S. & Roberts, A. Radioactive iodine in the study of thyroid physiology. 7. The use of radioactive iodine therapy in hyperthyroidism. JAMA 131, 81–86 (1946). Potential of radioiodine to treat thyroid disease.

    CAS  Google Scholar 

  94. Campbell, J. E., Robajdek, E. S. & Anthony, D. S. The metabolism of Ac-227 and its daughters Th-227 and Ra-223 by rats. Radiat. Res. 4, 294–302 (1956).

    CAS  PubMed  Google Scholar 

  95. Joshi, D. P., Seery, W. H., Goldberg, L. G. & Goldman, L. Evaluation of phosphorus 32 for intractable pain secondary to prostatic carcinoma metastasES. JAMA 193, 621–623 (1965).

    CAS  PubMed  Google Scholar 

  96. Harrison, G. E., Carr, T. E., Sutton, A. & Rundo, J. Plasma concentration and excretion of calcium-47, strontium-85, barium-133 and radium-223 following successive intravenous doses to a healthy man. Nature 209, 526–527 (1966).

    CAS  PubMed  Google Scholar 

  97. Foss, C. A. et al. Radiolabeled small-molecule ligands for prostate-specific membrane antigen: in vivo imaging in experimental models of prostate cancer. Clin. Cancer Res. 11, 4022–4028 (2005).

    CAS  PubMed  Google Scholar 

  98. Zechmann, C. M. et al. Radiation dosimetry and first therapy results with a 124I/131I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy. Eur. J. Nucl. Med. Mol. Imaging 41, 1280–1292 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Kong, G. & Hicks, R. J. Peptide receptor radiotherapy: current approaches and future directions. Curr. Treat. Options Oncol. 20, 77 (2019).

    PubMed  Google Scholar 

  100. Muller, C., Vlahov, I. R., Santhapuram, H. K. R., Leamon, C. P. & Schibli, R. Tumor targeting using Ga-67-DOTA-Bz-folate - investigations of methods to improve the tissue distribution of radiofolates. Nucl. Med. Biol. 38, 715–723 (2011).

    PubMed  Google Scholar 

  101. Muller, C., Struthers, H., Winiger, C., Zhernosekov, K. & Schibli, R. DOTA conjugate with an albumin-binding entity enables the first folic acid-targeted 177Lu-radionuclide tumor therapy in mice. J. Nucl. Med. 54, 124–131 (2013).

    CAS  PubMed  Google Scholar 

  102. Ambrosini, V., Fani, M., Fanti, S., Forrer, F. & Maecke, H. R. Radiopeptide imaging and therapy in Europe. J. Nucl. Med. 52, 42S–55S (2011).

    CAS  PubMed  Google Scholar 

  103. Song, H. & Sgouros, G. Radioimmunotherapy of solid tumors: searching for the right target. Curr. Drug Deliv. 8, 26–44 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Leaman Alcibar, O. et al. Time for radioimmunotherapy: an overview to bring improvements in clinical practice. Clin. Transl Oncol. 21, 992–1004 (2019).

    CAS  PubMed  Google Scholar 

  105. Larson, S. M., Carrasquillo, J. A. & Reynolds, J. C. Radioimmunodetection and radioimmunotherapy. Cancer Invest. 2, 363–381 (1984).

    CAS  PubMed  Google Scholar 

  106. Goldenberg, D. M. Targeting of cancer with radiolabeled antibodies. Prospects for imaging and therapy. Arch. Pathol. Lab. Med. 112, 580–587 (1988).

    CAS  PubMed  Google Scholar 

  107. Jeon, J. Review of therapeutic applications of radiolabeled functional nanomaterials. Int. J. Mol. Sci 20, 2323 (2019).

    CAS  PubMed Central  Google Scholar 

  108. Sofou, S. & Sgouros, G. Antibody-targeted liposomes in cancer therapy and imaging. Expert. Opin. Drug Deliv 5, 189–204 (2008).

    CAS  PubMed  Google Scholar 

  109. Lee, E. J., Chung, H. W., Jo, J. H. & So, Y. Radioembolization for the treatment of primary and metastatic liver cancers. Nucl. Med. Mol. Imaging 53, 367–373 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Wu, A. M. & Senter, P. D. Arming antibodies: prospects and challenges for immunoconjugates. Nat. Biotech. 23, 1137–1146 (2005).

    CAS  Google Scholar 

  111. Hu, S. Z. et al. Minibody: a novel engineered anti-carcinoembryonic antigen antibody fragment (single-chain Fv-CH3) which exhibits rapid, high-level targeting of xenografts. Cancer Res. 56, 3055–3061 (1996).

    CAS  PubMed  Google Scholar 

  112. Wu, A. M. et al. Tumor localization of anti-CEA single-chain Fvs: improved targeting by non-covalent dimers. Immunotechnology 2, 21–36 (1996).

    CAS  PubMed  Google Scholar 

  113. Cheung, N. K. V. et al. Single-chain Fv-streptavidin substantially improved therapeutic index in multistep targeting directed at disialoganglioside GD2. J. Nucl. Med. 45, 867–877 (2004).

    CAS  PubMed  Google Scholar 

  114. Boerman, O. C. et al. Pretargeting of renal cell carcinoma: improved tumor targeting with a bivalent chelate. Cancer Res. 59, 4400–4405 (1999).

    CAS  PubMed  Google Scholar 

  115. Chang, C. H. et al. Molecular advances in pretargeting radioimunotherapy with bispecific antibodies. Mol. Cancer Ther. 1, 553–563 (2002).

    CAS  PubMed  Google Scholar 

  116. McBride, W. J. et al. Bispecific antibody pretargeting PET (ImmunoPET) with an I-124-labeled hapten-peptide. J. Nucl. Med. 47, 1678–1688 (2006).

    CAS  PubMed  Google Scholar 

  117. Catz, B. et al. Treatment of cancer of the thyroid postoperatively with suppressive thyroid medication, radioactive iodine, and thyroid-stimulating hormone. Cancer 12, 371–383 (1959).

    CAS  PubMed  Google Scholar 

  118. Hamilton, J. G. & Soley, M. H. Studies in iodine metabolism of the thyroid gland in situ by the use of radio-iodine in normal subjects and in patients with various types of goiter. Am. J. Physiol. 131, 0135–0143 (1940).

    CAS  Google Scholar 

  119. Benua, R. S., Rawson, R. W., Sonenberg, M. & Cicale, N. R. Relation of radioiodine dosimetry to results and complications in treatment of metastatic thyroid cancer. Am. J. Roentgenol. Radium Ther. Nucl. Med. 87, 171–182 (1962).

    CAS  PubMed  Google Scholar 

  120. Maxon, H. R. et al. Relation between effective radiation dose and outcome of radioiodine therapy for thyroid cancer. N. Engl. J. Med. 309, 937–941 (1983).

    CAS  PubMed  Google Scholar 

  121. Livingood, J. J. & Seaborg, G. T. Radioactive iodine isotopes. Phys. Rev. 53, 1015 (1938).

    CAS  Google Scholar 

  122. Knapp, R. F. F. & Dash, A. Radiopharmaceuticals for Therapy - 2016. (Springer, 2016).

  123. Hertz, S., Roberts, A., Means, J. H. & Evans, R. D. Radioactive iodine as an indicator in thyroid physiology - Iodine collection by normal and hyperplastic thyroids in rabbits. Am. J. Physiol. 128, 565–576 (1940).

    Google Scholar 

  124. Cooper, D. S. et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19, 1167–1214 (2009).

    PubMed  Google Scholar 

  125. Fagin, J. A. & Wells, S. A. Jr. Biologic and clinical perspectives on thyroid cancer. N. Engl. J. Med. 375, 1054–1067 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Gao, W. et al. Internal radiotherapy using 32P colloid or microsphere for refractory solid tumors. Ann. Nucl. Med. 22, 653–660 (2008).

    PubMed  Google Scholar 

  127. Morris, M. J. et al. Radium-223 mechanism of action: implications for use in treatment combinations. Nat. Rev. Urol. 16, 745–756 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Leung, C. N. et al. Dose-dependent growth delay of breast cancer xenografts in the bone marrow of mice treated with 223Ra: the role of bystander effects and their potential for therapy. J. Nucl. Med. 61, 89–95 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Tombal, B. F. et al. Decreased fracture rate by mandating bone-protecting agents in the EORTC 1333/PEACE III trial comparing enzalutamide and Ra223 versus enzalutamide alone: an interim safety analysis. J. Clin. Oncol. 37, 5007 (2019).

    Google Scholar 

  130. Smith, M. R. et al. ERA 223: a phase 3 trial of radium-223 dichloride (Ra-223) in combination with abiraterone acetate (abiraterone) and prednisone in the treatment of asymptomatic or mildly symptomatic chemotherapy-naïve patients (pts) with bone predominant metastatic castration-resistant prostate cancer (mCRPC). J. Clin. Oncol. 33, TPS5082 (2015).

    Google Scholar 

  131. Dalla Volta, A., Formenti, A. M. & Berruti, A. Higher risk of fragility fractures in prostate cancer patients treated with combined radium-223 and abiraterone: prednisone may be the culprit. Eur. Urol. 75, 894–895 (2019).

    PubMed  Google Scholar 

  132. Sartor, O. Overview of samarium Sm 153 lexidronam in the treatment of painful metastatic bone disease. Rev. Urol. 6, S3–S12 (2004).

    PubMed  PubMed Central  Google Scholar 

  133. Anderson, P. M., Subbiah, V. & Rohren, E. In: Current Advances in Osteosarcoma. 291–304 (Springer International Publishing, 2014).

  134. Longo, J., Lutz, S. & Johnstone, C. Samarium-153-ethylene diamine tetramethylene phosphonate, a beta-emitting bone-targeted radiopharmaceutical, useful for patients with osteoblastic bone metastases. Cancer Manag. Res. 5, 235–242 (2013).

    PubMed  PubMed Central  Google Scholar 

  135. Chirby, D., Franck, S. & Troutner, D. E. Adsorption of 153Sm-EDTMP on calcium hydroxyapatite. Int. J. Radiat. Appl. Instrum. Part A Appl. Radiat. Isotopes 39, 495–499 (1988).

    CAS  Google Scholar 

  136. Eary, J. F. et al. Samarium-153-EDTMP biodistribution and dosimetry estimation. J. Nucl. Med. 34, 1031–1036 (1993).

    CAS  PubMed  Google Scholar 

  137. Goyal, J. & Antonarakis, E. S. Bone-targeting radiopharmaceuticals for the treatment of prostate cancer with bone metastases. Cancer Lett. 323, 135–146 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Simon, J. J. et al. Preclinical evaluation of Sm-153-DOTMP as a therapeutic bone-seeking radiopharmaceutical. J. Nucl. Med. 52, 1751 (2011).

    Google Scholar 

  139. Simón, J. et al. A preclinical investigation of the saturation and dosimetry of 153Sm-DOTMP as a bone-seeking radiopharmaceutical. Nucl. Med. Biol. 39, 770–776 (2012).

    PubMed  PubMed Central  Google Scholar 

  140. Schmidt, M., Hero, B. & Simon, T. I-131-mIBG therapy in neuroblastoma: established role and prospective applications. Clin. Transl Imaging 4, 87–101 (2016).

    Google Scholar 

  141. Schoot, R. A. et al. The role of 131I-metaiodobenzylguanidine (MIBG) therapy in unresectable and compromising localised neuroblastoma. Eur. J. Nucl. Med. Mol. Imaging 40, 1516–1522 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. George, S. L. et al. Individualized I-131-mIBG therapy in the management of refractory and relapsed neuroblastoma. Nucl. Med. Commun. 37, 466–472 (2016).

    PubMed  PubMed Central  Google Scholar 

  143. Eisenhut, M. M. W. in Handbook of Nuclear Chemistry. (eds Vértes, A. N. S., Klencsár, Z., Lovas, R. G., Rösch, F.) (Springer, 2011).

  144. Inaki, A. et al. A phase I clinical trial for [131I]meta-iodobenzylguanidine therapy in patients with refractory pheochromocytoma and paraganglioma: a study protocol. J. Med. Invest. 64, 205–209 (2017).

    PubMed  Google Scholar 

  145. Modak, S. et al. Arsenic trioxide as a radiation sensitizer for 131I-metaiodobenzylguanidine therapy: results of a phase II study. J. Nucl. Med. 57, 231–237 (2016).

    CAS  PubMed  Google Scholar 

  146. Shilkrut, M., Bar-Deroma, R., Bar-Sela, G., Berniger, A. & Kuten, A. Low-dose iodine-131 metaiodobenzylguanidine therapy for patients with malignant pheochromocytoma and paraganglioma: single center experience. Am. J. Clin. Oncol. 33, 79–82 (2010).

    CAS  PubMed  Google Scholar 

  147. Coleman, R. E. et al. Radiation dosimetry, pharmacokinetics, and safety of ultratrace Iobenguane I-131 in patients with malignant pheochromocytoma/paraganglioma or metastatic carcinoid. Cancer Biother. Radiopharm 24, 469–475 (2009).

    CAS  PubMed  Google Scholar 

  148. Gonias, S. et al. Phase II study of high-dose [131I]metaiodobenzylguanidine therapy for patients with metastatic pheochromocytoma and paraganglioma. J. Clin. Oncol. 27, 4162–4168 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Fitzgerald, P. A. et al. Malignant pheochromocytomas and paragangliomas: a phase II study of therapy with high-dose 131I-metaiodobenzylguanidine (131I-MIBG). Ann. NY Acad. Sci. 1073, 465–490 (2006).

    CAS  PubMed  Google Scholar 

  150. Sisson, J. C. et al. Treatment of malignant pheochromocytomas with 131-I metaiodobenzylguanidine and chemotherapy. Am. J. Clin. Oncol. 22, 364–370 (1999).

    CAS  PubMed  Google Scholar 

  151. Mundschenk, J., Kopf, D. & Lehnert, H. Therapy of malignant pheochromocytoma. Invitation to participate in a randomized multicenter study. Dtsch. medizinische Wochenschr. 123, 32–33 (1998).

    CAS  Google Scholar 

  152. Noto, R. B. et al. Phase 1 study of high-specific-activity I-131 MIBG for metastatic and/or recurrent pheochromocytoma or paraganglioma. J. Clin. Endocrinol. Metab. 103, 213–220 (2017).

    Google Scholar 

  153. Pinto, J. T. et al. Prostate-specific membrane antigen: a novel folate hydrolase in human prostatic carcinoma cells. Clin. Cancer Res. 2, 1445–1451 (1996).

    CAS  PubMed  Google Scholar 

  154. Heston, W. D. Characterization and glutamyl preferring carboxypeptidase function of prostate specific membrane antigen: a novel folate hydrolase. Urology 49 (Suppl. 3A), 104–112 (1997).

    CAS  PubMed  Google Scholar 

  155. Murphy, D. G., Sathianathen, N., Hofman, M. S., Azad, A. & Lawrentschuk, N. Where to next for theranostics in prostate cancer? Eur. Urol. Oncol. 2, 163–165 (2019).

    PubMed  Google Scholar 

  156. Tateishi, U. Prostate-specific membrane antigen (PSMA)–ligand positron emission tomography and radioligand therapy (RLT) of prostate cancer. Jap. J. Clin. Oncol. 50, 349–356 (2020).

    Google Scholar 

  157. Novakova, Z. et al. Design of composite inhibitors targeting glutamate carboxypeptidase II: the importance of effector functionalities. FEBS J. 283, 130–143 (2016).

    CAS  PubMed  Google Scholar 

  158. Banerjee, S. R. et al. 68Ga-labeled inhibitors of prostate-specific membrane antigen (PSMA) for imaging prostate cancer. J. Med. Chem. 53, 5333–5341 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Barinka, C. et al. Structural insight into the pharmacophore pocket of human glutamate carboxypeptidase II. J. Med. Chem. 50, 3267–3273 (2007).

    CAS  PubMed  Google Scholar 

  160. Bařinka, C., Rojas, C., Slusher, B. & Pomper, M. Glutamate carboxypeptidase II in diagnosis and treatment of neurologic disorders and prostate cancer. Curr. Med. Chem. 19, 856–870 (2012).

    PubMed  PubMed Central  Google Scholar 

  161. Kozikowski, A. P. et al. Synthesis of urea-based inhibitors as active site probes of glutamate carboxypeptidase II: efficacy as analgesic agents. J. Med. Chem. 47, 1729–1738 (2004). Early report on small-molecule PSMA inhibitors.

    CAS  PubMed  Google Scholar 

  162. Zhou, J., Neale, J. H., Pomper, M. G. & Kozikowski, A. P. NAAG peptidase inhibitors and their potential for diagnosis and therapy. Nat. Rev. Drug Discov. 4, 1015–1026 (2005).

    CAS  PubMed  Google Scholar 

  163. Wu, L. Y. et al. The molecular pruning of a phosphoramidate peptidomimetic inhibitor of prostate-specific membrane antigen. Bioorg. Med. Chem. 15, 7434–7443 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Liu, T., Toriyabe, Y., Kazak, M. & Berkman, C. E. Pseudoirreversible inhibition of prostate-specific membrane antigen by phosphoramidate peptidomimetics. Biochemistry 47, 12658–12660 (2008).

    CAS  PubMed  Google Scholar 

  165. Choy, C. J. et al. Lu-177-labeled phosphoramidate-based PSMA inhibitors: the effect of an albumin binder on biodistribution and therapeutic efficacy in prostate tumor-bearing mice. Theranostics 7, 1928–1939 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Hofman, M. S. et al. [177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study. Lancet Oncol. 19, 825–833 (2018). Efficacy and toxicity of anti-PSMA therapy in prostate cancer using lutetium-177.

    CAS  PubMed  Google Scholar 

  167. Derlin, T. & Schmuck, S. [177Lu]-PSMA-617 radionuclide therapy in patients with metastatic castration-resistant prostate cancer. Lancet Oncol. 19, e372 (2018).

    PubMed  Google Scholar 

  168. Rahbar, K., Ahmadzadehfar, H., Seifert, R. & Boegemann, M. [177Lu]-PSMA-617 radionuclide therapy in patients with metastatic castration-resistant prostate cancer. Lancet Oncol. 19, e371 (2018).

    PubMed  Google Scholar 

  169. Hofman, M. S., Violet, J., Hicks, R. J. & Sandhu, S. [177Lu]-PSMA-617 radionuclide therapy in patients with metastatic castration-resistant prostate cancer - Author’s reply. Lancet Oncol. 19, e373 (2018).

    PubMed  Google Scholar 

  170. Muzio, V. et al. Assessment of in vivo biodistribution and treatment efficacy of Lu-177 PSMA-R2 and Lu-177-PSMA-617 on mice bearing prostate cancer tumors. Eur. J. Nucl. Med. Mol. Imaging 46 (Suppl. 1), 17 (2019).

  171. Nedrow-Byers, J. R. et al. A phosphoramidate-based prostate-specific membrane antigen-targeted SPECT agent. Prostate 72, 904–912 (2012).

    CAS  PubMed  Google Scholar 

  172. Choy, C. J. et al. 177Lu-labeled phosphoramidate-based PSMA inhibitors: the effect of an Albumin Binder on biodistribution and therapeutic efficacy in prostate tumor-bearing mice. Theranostics 7, 1928–1939 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Gourni, E. & Henriksen, G. Metal-based PSMA radioligands. Molecules 22, 523 (2017).

    PubMed Central  Google Scholar 

  174. Wester, H.-J. & Schottelius, M. PSMA-targeted radiopharmaceuticals for imaging and therapy. Semin. Nucl. Med. 49, 302–312 (2019).

    PubMed  Google Scholar 

  175. Ross, J. F., Chaudhuri, P. K. & Ratnam, M. Differential regulation of folate receptor isoforms in normal and malignant tissues in vivo and in established cell lines. Physiologic and Clinical Implications. Cancer 73, 2432–2443 (1994).

    CAS  PubMed  Google Scholar 

  176. Cheung, A. et al. Targeting folate receptor alpha for cancer treatment. Oncotarget. 7, 52553–52574 (2016).

    PubMed  PubMed Central  Google Scholar 

  177. Kettenbach, K. et al. Comparison study of two differently clicked 18F-folates-lipophilicity plays a key role. Pharmaceuticals 11, 30 (2018).

    PubMed Central  Google Scholar 

  178. Siwowska, K. & Müller, C. Preclinical development of small-molecular-weight folate-based radioconjugates: a pharmacological perspective. Q. J. Nucl. Med. Mol. Imaging 59, 269–286 (2015).

    CAS  PubMed  Google Scholar 

  179. Siwowska, K. et al. Therapeutic potential of 47Sc in comparison to 177Lu and 90Y: preclinical investigations. Pharmaceutics 11, 424 (2019).

    CAS  PubMed Central  Google Scholar 

  180. Gupta, A. et al. Voxel-based dosimetry of iron oxide nanoparticle-conjugated 177Lu-labeled folic acid using SPECT/CT imaging of mice. Mol. Pharmaceutics. 16, 1498–1506 (2019).

    CAS  Google Scholar 

  181. Müller, C. et al. Direct in vitro and in vivo comparison of 161Tb and 177Lu using a tumour-targeting folate conjugate. Eur. J. Nucl. Med. Mol. Imaging 41, 476–485 (2014).

    PubMed  Google Scholar 

  182. Snyder, F. & Wood, R. Alkyl and alk-1-enyl ethers of glycerol in lipids from normal and neoplastic human tissues. Cancer Res. 29, 251–257 (1969).

    CAS  PubMed  Google Scholar 

  183. Snyder, F., Blank, M. L. & Morris, H. P. Occurrence and nature of O-alkyl and O-alk-I-enyl moieties of glycerol in lipids of Morris transplanted hepatomas and normal rat liver. Biochim. Biophys. Acta 176, 502–510 (1969).

    CAS  PubMed  Google Scholar 

  184. Counsell, R. E., Schwendner, S. W., Meyer, K. L., Haradahira, T. & Gross, M. D. Tumor visualization with a radioiodinated phospholipid ether. J. Nucl. Med. 31, 332–336 (1990).

    CAS  PubMed  Google Scholar 

  185. Meyer, K. L., Schwendner, S. W. & Counsell, R. E. Potential tumor or organ-imaging agents. 30. Radioiodinated phospholipid ethers. J. Med. Chem. 32, 2142–2147 (1989).

    CAS  PubMed  Google Scholar 

  186. Pinchuk, A. N. et al. Synthesis and structure−activity relationship effects on the tumor avidity of radioiodinated phospholipid ether analogues. J. Med. Chem. 49, 2155–2165 (2006).

    CAS  PubMed  Google Scholar 

  187. Weichert, J. P. et al. Alkylphosphocholine analogs for broad-spectrum cancer imaging and therapy. Sci. Transl Med. 6, 240ra75 (2014). Phosphocholine-based RPT.

    PubMed  PubMed Central  Google Scholar 

  188. Baiu, D. C. et al. Targeted molecular radiotherapy of pediatric solid tumors using a radioiodinated alkyl-phospholipid ether analog. J. Nucl. Med. 59, 244–250 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Hall, L. T. et al. PET/CT imaging of the diapeutic alkylphosphocholine analog I-124-CLR1404 in high and low-grade brain tumors. Am. J. Nucl. Med. Mol. Imaging 7, 157–166 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Hall, L. T. et al. I-124 CLR1404 PET/CT in high-grade primary and metastatic brain tumors. Mol. Imaging Biol. 22, 434–443 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Morris, Z. S. et al. Therapeutic combination of radiolabeled CLR1404 with external beam radiation in head and neck cancer model systems. Radiother. Oncol. 116, 504–509 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Bodei, L., Kwekkeboom, D. J., Kidd, M., Modlin, I. M. & Krenning, E. P. Radiolabeled somatostatin analogue therapy of gastroenteropancreatic cancer. Semin. Nucl. Med. 46, 225–238 (2016).

    PubMed  Google Scholar 

  193. Fani, M., Nicolas, G. P. & Wild, D. Somatostatin receptor antagonists for imaging and therapy. J. Nucl. Med. 58, 61S–66S (2017). Trial that demonstrates the greater tumour uptake and absorbed dose with somatostatin receptor antagonists compared with agonists.

    CAS  PubMed  Google Scholar 

  194. Strosberg, J. et al. Phase 3 trial of Lu-177-dotatate for midgut neuroendocrine tumors. N. Engl. J. Med. 376, 125–135 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Strosberg, J. et al. Health-related quality of life in patients with progressive midgut neuroendocrine tumors treated with 177Lu-Dotatate in the phase III NETTER-1 trial. J. Clin. Oncol. 36, 2578–2584 (2018). Trial that led to FDA approval of 177Lu-DOTATATE.

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Kwekkeboom, D. J. et al. Treatment with the radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate: toxicity, efficacy, and survival. J. Clin. Oncol. 26, 2124–2130 (2008).

    CAS  PubMed  Google Scholar 

  197. Atcher, R. W., Friedman, A. M. & Hines, J. J. An improved generator for the production of Pb-212 and Bi-212 from Ra-224. Appl. Radiat. Isot. 39, 283–286 (1988).

    CAS  Google Scholar 

  198. Delpassand, E. et al. First clinical experience using targeted alpha-emitter therapy with Pb-212-DOTAMTATE (AlphaMedix TM) in patients with SSTR(+) neuroendocrine tumors. J. Nucl. Med. 60, (2019).

  199. Stallons, T. A. R., Saidi, A., Tworowska, I., Delpassand, E. S. & Torgue, J. J. Preclinical Investigation of Pb-212-DOTAMTATE for peptide receptor radionuclide therapy in a neuroendocrine tumor model. Mol. Cancer Ther 18, 1012–1021 (2019).

    CAS  PubMed  Google Scholar 

  200. Bodei, L. et al. Long-term tolerability of PRRT in 807 patients with neuroendocrine tumours: the value and limitations of clinical factors. Eur. J. Nucl. Med. Mol. Imaging 42, 5–19 (2015). Study that demonstrates the toxicity profile of PRRT with 90Y, 177Lu or their combination in a large series of patients.

    CAS  PubMed  Google Scholar 

  201. Reidy-Lagunes, D. et al. Phase I trial of well-differentiated neuroendocrine tumors (NETs) with radiolabeled somatostatin antagonist 177Lu-satoreotide tetraxetan. Clin. Cancer Res. 25, 6939–6947 (2019).

    PubMed  PubMed Central  Google Scholar 

  202. Jensen, R. T., Battey, J. F., Spindel, E. R. & Benya, R. V. International Union of Pharmacology. LXVIII. Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling, and functions in normal and disease states. Pharmacol. Rev. 60, 1–42 (2008).

    CAS  PubMed  Google Scholar 

  203. Baratto, L., Jadvar, H. & Iagaru, A. Prostate cancer theranostics targeting gastrin-releasing peptide receptors. Mol. Imaging Biol. 20, 501–509 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Pooja, D., Gunukula, A., Gupta, N., Adams, D. J. & Kulhari, H. Bombesin receptors as potential targets for anticancer drug delivery and imaging. Int. J. Biochem. Cell Biol. 114, 105567 (2019).

    CAS  PubMed  Google Scholar 

  205. Morgat, C. et al. Comparison of the binding of the gastrin-releasing peptide receptor (GRP-R) antagonist 68Ga-RM2 and 18F-FDG in breast cancer samples. PLoS ONE 14, e0210905 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Abouzayed, A. et al. Synthesis and preclinical evaluation of radio-iodinated GRPR/PSMA bispecific heterodimers for the theranostics application in prostate cancer. Pharmaceutics 11, 358 (2019).

    CAS  PubMed Central  Google Scholar 

  207. Liolios, C., Sachpekidis, C., Schäfer, M. & Kopka, K. Bispecific radioligands targeting prostate-specific membrane antigen and gastrin-releasing peptide receptors on the surface of prostate cancer cells. J. Label. Comp. Radiopharm. 62, 510–522 (2019).

    CAS  Google Scholar 

  208. Baratto, L., Duan, H., Maecke, H. R. & Iagaru, A. Imaging the distribution of gastrin releasing peptide receptors in cancer. J. Nucl. Med 61, 792–798 (2020).

    CAS  PubMed  Google Scholar 

  209. Bodei, L. et al. Lu-177-AMBA bombesin analogue in hormone refractory prostate cancer patients: a phase I escalation study with single-cycle administrations. Eur. J. Nucl. Med. Mol. Imaging 34, S221 (2007).

  210. Cescato, R. et al. Bombesin receptor antagonists may be preferable to agonists for tumor targeting. J. Nucl. Med. 49, 318–326 (2008). Comparative in vitro/in vivo study indicating that GRPR antagonists may be superior targeting agents to GRPR agonists.

    CAS  PubMed  Google Scholar 

  211. Dalm, S. U. et al. 68Ga/177Lu-NeoBOMB1, a novel radiolabeled GRPR antagonist for theranostic use in oncology. J. Nucl. Med. 58, 293–299 (2017).

    CAS  PubMed  Google Scholar 

  212. Kurth, J. et al. First-in-human dosimetry of gastrin-releasing peptide receptor antagonist [177Lu]Lu-RM2: a radiopharmaceutical for the treatment of metastatic castration-resistant prostate cancer. Eur. J. Nucl. Med. Mol. Imaging 47, 123–135 (2020).

    CAS  PubMed  Google Scholar 

  213. Thomas, V. A. & Balthasar, J. P. Understanding inter-individual variability in monoclonal antibody disposition. Antibodies 8, E56 (2019).

    PubMed  Google Scholar 

  214. Wohlrab, J. Pharmacokinetic characteristics of therapeutic antibodies. JDDG 13, 530–534 (2015).

    PubMed  Google Scholar 

  215. Kohler, G. & Milstein, C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256, 495–497 (1975). Nobel Prize-winning work to produce antibodies from a single clone, an essential precursor to antibody-based RPT.

    CAS  PubMed  Google Scholar 

  216. Larson, S. M. et al. Imaging of melanoma with I-131-labeled monoclonal antibodies. J. Nucl. Med. 24, 123–129 (1983). Among the earliest reports of antibody-based cancer imaging; precursor to antibody-based RPT.

    CAS  PubMed  Google Scholar 

  217. Mach, J. P. et al. Tumor localization in patients by radiolabeled monoclonal antibodies against colon carcinoma. Cancer Res. 43, 5593–5600 (1983). Among the earliest reports of antibody-based cancer imaging; precursor to antibody-based RPT.

    CAS  PubMed  Google Scholar 

  218. Colcher, D. et al. Radiolabeled monoclonal-antibody B72.3 localization in metastatic lesions of colorectal-cancer patients. Nucl. Med. Biol. 14, 251 (1987).

    CAS  Google Scholar 

  219. Goldenberg, D. M. et al. Use of radiolabeled antibodies to carcinoembryonic antigen for the detection and localization of diverse cancers by external photoscanning. N. Engl. J. Med. 298, 1384–1386 (1978). Among the earliest reports of antibody-based cancer imaging; precursor to antibody-based RPT.

    CAS  PubMed  Google Scholar 

  220. Mahe, M. A. et al. A phase II study of intraperitoneal radioimmunotherapy with iodine-131-labeled monoclonal antibody OC-125 in patients with residual ovarian carcinoma. Clin. Cancer Res. 5 (Suppl. 10), 3249–3253 (1999).

    Google Scholar 

  221. Cassaday, R. D. et al. Phase I study of a CD45-targeted antibody-radionuclide conjugate for high-risk lymphoma. Clin. Cancer Res. 25, 6932–6938 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. Tomlinson, B. K. et al. Rapid reduction of peripheral blasts in older patients with refractory acute myeloid leukemia (AML) using re-induction with single agent anti-CD45 targeted iodine (I-131) apamistamab Iomab-B radioimmunotherapy in the phase III SIERRA trial. Clin. Lymphoma Myeloma Leukemia 19, S232 (2019).

    Google Scholar 

  223. Pagel, J. M. et al. Allogeneic hematopoietic cell transplantation after conditioning with I-131-anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome. Blood 114, 5444–5453 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. Gopal, A. K., Pagel, J. M., Fromm, J. R., Wilbur, S. & Press, O. W. I-131 anti-CD45 radioimmunotherapy effectively targets and treats T-cell non-Hodgkin lymphoma. Blood 113, 5905–5910 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  225. Mawad, R. et al. Radiolabeled anti-CD45 antibody with reduced-intensity conditioning and allogeneic transplantation for younger patients with advanced acute myeloid leukemia or myelodysplastic syndrome. Biol. Blood Marrow Transplant. 20, 1363–1368 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. Tomlinson, B. et al Rapid reduction of peripheral blasts in older patients with refractory acute myeloid leukemia (AML) using reinduction with single agent anti-CD45 targeted iodine (I-131) apamistamab Iomab-B radioimmunotherapy in the phase III SIERRA trial. J. Clin. Oncol. 37 (Suppl. 15), 7048 (2019).

  227. Griffeth, L. et al. Personalized dosimetry using I-131-anti-CD45-apamistamab (Iomab-B) prior to high-dose myeloablative radioimmunotherapy for hematopoietic stem cell transplant (HCT) in active, relapsed, or refractory acute myelogenous leukemia: novel re-induction and targeted conditioning feasibility and engraftment results from the SIERRA trial. J. Nucl. Med. 60 (Suppl. 1), 434 (2019).

  228. Pandit-Taskar, N. et al. Optimizing dosimetry imaging in high-dose radioimmunotherapy using the novel, anti-CD45 re-induction and targeted conditioning agent iodine (I-131) apamistamab Iomab-B in patients 55 years or older with active, relapsed or refractory acute myeloid leukemia (SIE phase III trial). J. Nucl. Med. 60 (Suppl. 1), 433 (2019).

  229. Schwartz, M. A. et al. Dose-escalation trial of M195 labeled with I-131 for cytoreduction and marrow ablation in relapsed or refractory myeloid leukemias. J. Clin. Oncol. 11, 294–303 (1993).

    CAS  PubMed  Google Scholar 

  230. Pagel, J. M. et al. Allogeneic hematopoietic cell transplantation after conditioning with 131I-anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome. Blood 114, 5444–5453 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. Press, O. W. et al. Phase II trial of 131I-B1 (anti-CD20) antibody therapy with autologous stem cell transplantation for relapsed B cell lymphomas. Lancet 346, 336–340 (1995). Use of RPT for bone marrow ablation in preparation for transplantation.

    CAS  PubMed  Google Scholar 

  232. Orozco, J. J. et al. Anti-CD45 radioimmunotherapy using At-211 with bone marrow transplantation prolongs survival in a disseminated murine leukemia model. Blood 121, 3759–3767 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  233. Li, Y. W. et al. cGMP production of astatine-211-labeled anti-CD45 antibodies for use in allogeneic hematopoietic cell transplantation for treatment of advanced hematopoietic malignancies. Plos ONE 13, e0205135 (2018).

    PubMed  PubMed Central  Google Scholar 

  234. Scheinberg, D. A. et al. A phase I trial of monoclonal antibody M195 in acute myelogenous leukemia: specific bone marrow targeting and internalization of radionuclide. J. Clin. Oncol. 9, 478–490 (1991).

    CAS  PubMed  Google Scholar 

  235. Sgouros, G. et al. Pharmacokinetics and dosimetry of an alpha-particle emitter labeled antibody: 213Bi-HuM195 (anti-CD33) in patients with leukemia. J. Nucl. Med. 40, 1935–1946 (1999). Dosimetry for α-emitter RPT in humans; one of the first such reports.

    CAS  PubMed  Google Scholar 

  236. McDevitt, M. R., Finn, R. D., Sgouros, G., Ma, D. & Scheinberg, D. A. An 225Ac/213Bi generator system for therapeutic clinical applications: construction and operation. Appl. Radiat. Isot. 50, 895–904 (1999).

    CAS  PubMed  Google Scholar 

  237. McDevitt, M. R., Finn, R. D., Ma, D., Larson, S. M. & Scheinberg, D. A. Preparation of alpha-emitting 213Bi-labeled antibody constructs for clinical use. J. Nucl. Med. 40, 1722–1727 (1999).

    CAS  PubMed  Google Scholar 

  238. Kolbert, K. S. et al. Parametric images of antibody pharmacokinetics in Bi213-HuM195 therapy of leukemia. J. Nucl. Med. 42, 27–32 (2001).

    CAS  PubMed  Google Scholar 

  239. Rosenblat, T. L. et al. Sequential cytarabine and alpha-particle immunotherapy with bismuth-213-lintuzumab (HuM195) for acute myeloid leukemia. Clin. Cancer Res. 16, 5303–5311 (2010). Clinical α-particle therapy.

    CAS  PubMed  PubMed Central  Google Scholar 

  240. Jurcic, J. G. Targeted alpha-particle therapy for hematologic malignancies. J. Med. Imaging Radiat. Sci 50, S53–S57 (2019).

    PubMed  Google Scholar 

  241. Jurcic, J. G. et al. Phase I trial of the targeted alpha-particle nano-generator actinium-225 (225Ac-lintuzumab) (anti-CD33; HuM195) in acute myeloid leukemia (AML). J. Clin. Oncol. 29, 6516 (2011). Clinical α-particle therapy.

    Google Scholar 

  242. Jurcic, J. G. et al. Phase I trial of the targeted alpha-particle nano-generator actinium-225 (225Ac)-lintuzumab (anti-CD33) in combination with low-dose cytarabine (LDAC) for older patients with untreated acute myeloid leukemia (AML). Blood 122, 1460 (2013).

    Google Scholar 

  243. Jurcic, J. G. Targeted alpha-particle therapy for hematologic malignancies. Semin. Nucl. Med. 50, 152–161 (2020).

    PubMed  Google Scholar 

  244. Berger, M. S. et al. Actinium labeled daratumumab demonstrates enhanced killing of multiple myeloma cells over naked daratumumab. Blood 130, (2017).

  245. Dadachova, E. et al. Ac-225-CD38 antibody targeting is effective and well tolerated in experimental models of lymphoma and multiple myeloma. J. Nucl. Med. 60 (Suppl. 1), 1410 (2019).

  246. Juergens, R. A. et al. A phase I study of Ac-225 -FPI-1434 radioimmunotherapy in patients with IGF-1R expressing solid tumors (Poster). J. Clin. Oncol. 37, TPS3152 (2019).

  247. Hagemann, U. B. et al. Advances in precision oncology: targeted thorium-227 conjugates as a new modality in targeted alpha therapy. Cancer Biother. Radiopharm https://doi.org/10.1089/cbr.2020.3568 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  248. Hagemann, U. B. et al. A novel high energy alpha pharmaceutical: in vitro and in vivo potency of a mesothelin-targeted thorium-227 conjugate (TTC) in a model of bone disease. Cancer Res. 76, 591 (2016).

  249. Hagemann, U. B. et al. Mesothelin-targeted thorium-227 conjugate (MSLN-TTC): preclinical evaluation of a new targeted alpha therapy for mesothelin-positive cancers. Clin. Cancer Res. 25, 4723–4734 (2019).

    CAS  PubMed  Google Scholar 

  250. Hammer, S. et al. Preclinical pharmacology of the PSMA-targeted thorium-227 conjugate PSMA-TTC: a novel targeted alpha therapeutic for the treatment of prostate cancer. Cancer Res. https://doi.org/10.1158/1538-7445.AM2017-5200 (2017).

  251. Hammer, S. et al. Preclinical efficacy of a PSMA-targeted thorium-227 conjugate (PSMA-TTC), a targeted alpha therapy for prostate cancer. Clin. Cancer Res. 26, 1985–1996 (2020).

    CAS  PubMed  Google Scholar 

  252. Grant, D. et al. Pharmacokinetics and dosimetry of BAY 1862864, an alpha-emitting targeted thorium conjugate (CD22-TTC) in the Cynomolgus monkey. Eur. J. Nucl. Med. Mol. Imaging 45, S124 (2018).

    Google Scholar 

  253. Karlsson, J. et al. HER2-targeted thorium-227 conjugate (HER2-TTC): efficacy in a HER2 positive orthotopic bone model. Cancer Res. https://doi.org/10.1158/1538-7445.AM2017-5857 (2017).

  254. Karlsson, J. et al. HER2-targeted thorium-227 conjugate (HER2-TTC): efficacy in preclinical models of trastuzumab and T-DM1 resistance. Cancer Res. https://doi.org/10.1158/1538-7445.AM2017-5859 (2017).

  255. Karlsson, J. et al. In vitro and in vivo activity of a HER2-targeted thorium-227 conjugate (HER2-TTC) in HER2 low expressing and T-DM1/trastuzumab resistant preclinical mouse models. Eur. J. Cancer 103, E122 (2018).

    Google Scholar 

  256. Wickstroem, K. et al. Synergistic effect of a HER2 targeted thorium-227 conjugate in combination with olaparib in a BRCA2 deficient xenograft model. Pharmaceuticals 12, 155 (2019).

    CAS  PubMed Central  Google Scholar 

  257. Waldmann, T. ABCs of radioisotopes used for radioimmunotherapy: alpha- and beta-emitters. Leuk. Lymphoma. 44, S107–S113 (2003).

    CAS  PubMed  Google Scholar 

  258. Wahl, R. L. et al. Iodine-131 anti-B1 antibody for B-cell lymphoma: an update on the Michigan phase I experience. J. Nucl. Med. 39 (Suppl. 8), 21–27 (1998).

    Google Scholar 

  259. Wahl, R. L. Iodine-131 anti-B1 antibody therapy in non-Hodgkin’s lymphoma: dosimetry and clinical implications. J. Nucl. Med. 39 (Suppl. 8), 1 (1998).

    Google Scholar 

  260. Wahl, R. L., Kroll, S. & Zasadny, K. R. Patient-specific whole-body dosimetry: principles and a simplified method for clinical implementation. J. Nucl. Med. 39 (Suppl. 8), 14–20 (1998).

    Google Scholar 

  261. Witzig, T. E. et al. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin’s lymphoma. J. Clin. Oncol. 20, 3262–3269 (2002).

    CAS  PubMed  Google Scholar 

  262. Davis, T. A. et al. Results of a randomized study of Bexxar (TM) (tositumomab and iodine I 131 tositumomab) vs. unlabeled tositumomab in patients with relapsed or refractory low-grade or transformed non-Hodgkin’s lymphoma (NHL). Blood 98, 843A (2001).

    Google Scholar 

  263. Wahl, R. L. The clinical importance of dosimetry in radioimmunotherapy with tositumomab and iodine I 131 tositumomab. Semin. Oncol. 30, 31–38 (2003).

    CAS  PubMed  Google Scholar 

  264. Baxter, L. T. & Jain, R. K. Transport of fluid and macromolecules in tumors. IV. A microscopic model of the perivascular distribution. Microvasc. Res. 41, 252–272 (1991).

    CAS  PubMed  Google Scholar 

  265. Jain, R. K. & Baxter, L. T. Mechanisms of heterogeneous distribution of monoclonal antibodies and other macromolecules in tumors: significance of elevated interstitial pressure. Cancer Res. 48, 7022–7032 (1988).

    CAS  PubMed  Google Scholar 

  266. Jain, R. K. Transport of molecules across tumor vasculature. Cancer Metastasis Rev. 6, 559–593 (1987).

    CAS  PubMed  Google Scholar 

  267. Saga, T. et al. Targeting cancer micrometastases with monoclonal antibodies: a binding-site barrier. Proc. Natl Acad. Sci. USA 92, 8999–9003 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  268. van Osdol, W., Fujimori, K. & Weinstein, J. N. An analysis of monoclonal antibody distribution in microscopic tumor nodules: consequences of a “binding site barrier”. Cancer Res. 51, 4776–4784 (1991).

    PubMed  Google Scholar 

  269. Fujimori, K., Covell, D. G., Fletcher, J. E. & Weinstein, J. N. A modeling analysis of monoclonal antibody percolation through tumors: a binding-site barrier. J. Nucl. Med. 31, 1191–1198 (1990).

    CAS  PubMed  Google Scholar 

  270. Sgouros, G. Plasmapheresis in radioimmunotherapy of micrometastases: a mathematical modeling and dosimetrical analysis [see comments]. J. Nucl. Med. 33, 2167–2179 (1992).

    CAS  PubMed  Google Scholar 

  271. Jaggi, J. S. et al. Improved tumor imaging and therapy via i.v. IgG-mediated time-sequential modulation of neonatal Fc receptor. J. Clin. Invest 117, 2422–2430 (2007).

    CAS  PubMed  Google Scholar 

  272. Goodwin, D. A., Meares, C. F. & Osen, M. Biological properties of biotin-chelate conjugates for pretargeted diagnosis and therapy with the avidin/biotin system. J. Nucl. Med. 39, 1813–1818 (1998). Initial approach to separating radionuclide delivery from cancer targeting to reduce haematological toxicity.

    CAS  PubMed  Google Scholar 

  273. Verhoeven, M., Seimbille, Y. & Dalm, S. U. Therapeutic applications of pretargeting. Pharmaceutics 11, 434 (2019).

    CAS  PubMed Central  Google Scholar 

  274. Liapi, E. & Geschwind, J.-F. H. Intra-arterial therapies for hepatocellular carcinoma: where do we stand? Ann. Surg. Oncol. 17, 1234–1246 (2010).

    PubMed  Google Scholar 

  275. Lewandowski, R. J., Geschwind, J.-F., Liapi, E. & Salem, R. Transcatheter intraarterial therapies: rationale and overview. Radiology 259, 641–657 (2011).

    PubMed  PubMed Central  Google Scholar 

  276. Lewandowski, R. J. & Salem, R. Yttrium-90 radioembolization of hepatocellular carcinoma and metastatic disease to the liver. Semin. Intervent. Radiol. 23, 64–72 (2006).

    PubMed  PubMed Central  Google Scholar 

  277. Riaz, A., Awais, R. & Salem, R. Side effects of yttrium-90 radioembolization. Front. Oncol. 4, 198 (2014).

    PubMed  PubMed Central  Google Scholar 

  278. Van Der Gucht, A. et al. Resin versus glass microspheres for 90Y transarterial radioembolization: comparing survival in unresectable hepatocellular carcinoma using pretreatment partition model dosimetry. J. Nucl. Med. 58, 1334–1340 (2017).

    Google Scholar 

  279. Biederman, D. M. et al. Outcomes of radioembolization in the treatment of hepatocellular carcinoma with portal vein invasion: resin versus glass microspheres. J. Vasc. Intervent. Radiol. 27, 812–21 (2016).

    Google Scholar 

  280. Mumper, R. J., Ryo, U. Y. & Jay, M. Neutron-activated holmium-166-poly (L-lactic acid) microspheres - a potential agent for the internal radiation-therapy of hepatic-tumors. J. Nucl. Med. 32, 2139–2143 (1991).

    CAS  PubMed  Google Scholar 

  281. Smits, M. L. J. et al. Holmium-166 radioembolisation in patients with unresectable, chemorefractory liver metastases (HEPAR trial): a phase 1, dose-escalation study. Lancet Oncol. 13, 1025–1034 (2012).

    CAS  PubMed  Google Scholar 

  282. Arranja, A. G., Hennink, W. E., Chassagne, C., Denkova, A. G. & Nijsen, J. F. W. Preparation and characterization of inorganic radioactive holmium-166 microspheres for internal radionuclide therapy. Mater. Sci. Eng. C Mater. Biol. Applications. 106, 110244 (2020).

    CAS  Google Scholar 

  283. Wang, X.-M. et al. Preventive effect of regional radiotherapy with phosphorus-32 glass microspheres in hepatocellular carcinoma recurrence after hepatectomy. World J. Gastroenterol. 14, 518–523 (2008).

    PubMed  PubMed Central  Google Scholar 

  284. Jeong, J. M. & Chung, J.-K. Therapy with 188Re-labeled radiopharmaceuticals: an overview of promising results from initial clinical trials. Cancer Biother. Radiopharm. 18, 707–717 (2003).

    CAS  PubMed  Google Scholar 

  285. Bretagne, J. F. et al. Hepatic artery injection of I-131-labeled lipiodol. Part II. Preliminary results therapeutic use patients Hepatocellular carcinoma liver metastases. Radiology 168, 547–550 (1988).

    CAS  PubMed  Google Scholar 

  286. Raoul, J. L. et al. Hepatic artery injection of I-131-labeled lipiodol. Part I. Biodistribution study results in patients with hepatocellular carcinoma and liver metastases. Radiology 168, 541–545 (1988).

    CAS  PubMed  Google Scholar 

  287. Raoul, J. I. et al. Internal radiation therapy for hepatocellular carcinoma. Results of a French multicenter phase II trial of transarterial injection of iodine 131-labeled Lipiodol. Cancer 69, 346–352 (1992).

    CAS  PubMed  Google Scholar 

  288. Raoul, J. L. et al. Randomized controlled trial for hepatocellular carcinoma with portal vein thrombosis: intra-arterial iodine-131-iodized oil versus medical support. J. Nucl. Med. 35, 1782–1787 (1994).

    CAS  PubMed  Google Scholar 

  289. Schwarz, L. et al. Adjuvant I-131 Lipiodol after resection or radiofrequency ablation for hepatocellular carcinoma. World J. Surg. 40, 1941–1950 (2016).

    PubMed  Google Scholar 

  290. Lau, W. Y. et al. Adjuvant intra-arterial lipiodol-iodine-131 for resectable hepatocellular carcinoma: a prospective randomised trial. Lancet 353, 797–801 (1999).

    CAS  PubMed  Google Scholar 

  291. Lau, W. Y., Lai, E. C. H., Leung, T. W. T. & Yu, S. C. H. Adjuvant intra-arterial iodine-131-labeled lipiodol for resectable hepatocellular carcinoma: a prospective randomized trial-update on 5-year and 10-year survival. Ann. Surg. 247, 43–48 (2008).

    PubMed  Google Scholar 

  292. Berenson, A. Market Forces Cited in Lymphoma Drugs’ Disuse. New York Times https://www.nytimes.com/2007/07/14/health/14lymphoma.html (2007).

  293. Mercadante, S. & Fulfaro, F. Management of painful bone metastases. Curr. Opin. Oncol. 19, 308–314 (2007).

    PubMed  Google Scholar 

  294. John, K. U. S. DOE tri-lab production effort to provide accelerator-produced 225Ac for radiotherapy: 2019 update. J. Nucl. Med. 60, 1612 (2019).

    Google Scholar 

  295. Hoehr, C. et al. Medical isotope production at TRIUMF – from imaging to treatment. Phys. Procedia. 90, 200–208 (2017).

    CAS  Google Scholar 

  296. Karimian, A., Ji, N. T., Song, H. & Sgouros, G. Mathematical modeling of pre-clinical alpha-emitter radiopharmaceutical therapy. Cancer Res. https://doi.org/10.1158/0008-5472.CAN-19-2553 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  297. Eckerman, K. & Endo, A. ICRP publication 107. Nuclear decay data for dosimetric calculations. Ann. ICRP 38, 7–96 (2007).

    Google Scholar 

  298. Papadimitroulas, P., Loudos, G., Nikiforidis, G. C. & Kagadis, G. C. A dose point kernel database using GATE Monte Carlo simulation toolkit for nuclear medicine applications: comparison with other Monte Carlo codes. Med. Phys. 39, 5238–5247 (2012).

    CAS  PubMed  Google Scholar 

  299. Simpkin, D. J. & Mackie, T. R. EGS4 Monte-Carlo determination of the beta-dose kernel in water. Med. Phys. 17, 179–186 (1990).

    CAS  PubMed  Google Scholar 

  300. [No authors listed.] Report 90: Key data for ionizing-radiation dosimetry: measurement standards and applications. J. Int. Comm. Rad. Units Meas. https://doi.org/10.1093/jicru/ndw043 (2016).

  301. Schlom, J. et al. Monoclonal antibody-based therapy of a human tumor xenograft with a 177lutetium-labeled immunoconjugate. Cancer Res. 51, 2889–2896 (1991).

    CAS  PubMed  Google Scholar 

  302. Kopka, K., Benešová, M., Barinka, C., Haberkorn, U. & Babich, J. Glu-ureido–based inhibitors of prostate-specific membrane antigen: lessons learned during the development of a novel class of low-molecular-weight theranostic radiotracers. J. Nucl. Med. 58, 17S–26S (2017).

    CAS  PubMed  Google Scholar 

  303. Maurer, T., Eiber, M., Schwaiger, M. & Gschwend, J. E. Current use of PSMA–PET in prostate cancer management. Nat. Rev. Urol. 13, 226–235 (2016).

    CAS  PubMed  Google Scholar 

  304. Muller, C. & Schibli, R. Folic acid conjugates for nuclear imaging of folate receptor-positive cancer. J. Nucl. Med. 52, 1–4 (2011).

    PubMed  Google Scholar 

  305. Larson, S. M., Carrasquillo, J. A., Cheung, N. K. & Press, O. W. Radioimmunotherapy of human tumours. Nat. Rev. Cancer 15, 347–360 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  306. Loevinger, R. & Berman, M. A schema for calculating the absorbed dose from biologically distributed radionuclides. MIRD pamphlet no. 1. J. Nucl. Med. 9, 5 (1968).

    Google Scholar 

  307. Ljungberg, M. et al. MIRD pamphlet no. 26: joint EANM/MIRD guidelines for quantitative 177Lu SPECT applied for dosimetry of radiopharmaceutical therapy. J. Nucl. Med. 57, 151–162 (2016).

    CAS  PubMed  Google Scholar 

  308. Prideaux, A. R. et al. Three-dimensional radiobiologic dosimetry: application of radiobiologic modeling to patient-specific 3-dimensional imaging-based internal dosimetry. J. Nucl. Med. 48, 1008–1016 (2007).

    PubMed  Google Scholar 

  309. Sgouros, G. et al. Three-dimensional imaging-based radiobiological dosimetry. Semin. Nucl. Med. 38, 321–334 (2008).

    PubMed  PubMed Central  Google Scholar 

  310. Sgouros, G. et al. Treatment planning for internal radionuclide therapy: three-dimensional dosimetry for nonuniformly distributed radionuclides. J. Nucl. Med. 31, 1884–1891 (1990). Imaging-based patient specific dosimetry for RPT treatment planning.

    CAS  PubMed  Google Scholar 

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Acknowledgements

G.S. acknowledges NIH grants R01CA116477 and R01CA187037.

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Authors and Affiliations

  1. Johns Hopkins University School of Medicine, Baltimore, MD, USA

    George Sgouros & Jessie R. Nedrow

  2. Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Lisa Bodei & Michael R. McDevitt

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  1. George Sgouros
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Correspondence to George Sgouros.

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Competing interests

G.S. is a founder of and holds equity in Radiopharmaceutical Imaging and Dosimetry LLC (Rapid). He serves as a member of Rapid’s Board of Directors; this arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. M.M. was a consultant for Actinium Pharmaceuticals, Regeneron, Progenics, Bridge Medicine and General Electric. Memorial Sloan Kettering has filed for IP protection for inventions of M.M. related to alpha particle technology. L.B. was a non-paid consultant for Advanced Accelerator Applications (AAA), Ipsen, Clovis, ITM and Curium, and receives research support from AAA. Johns Hopkins University has filed for IP protection for inventions of J.N. related to alpha particle technology.

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Glossary

Radionuclides

Interchangeable with ‘radioactive atoms’, ‘radioactive elements’ and ‘radioactive isotopes’. Although these are all correct, ‘radionuclide’ (not ‘radionucleotide’) is the preferred term in the context of nuclear medicine, in general, and radiopharmaceutical therapy, in particular.

β-Particles

Light, energetic electrons that are either positively or negatively charged and emitted spontaneously from atomic nuclei during a nuclear transformation of many radionuclides. These particles are characterized by a spectrum of energies and associated ranges, typically characterized as the maximum or end-point energy or range.

α-Particles

Positively charged, heavy particles ejected spontaneously from the nucleus of some radionuclides that are identical to a helium nucleus (mass number of 4 and electrical charge of +2). The DNA damage resulting from these short-range particles per unit of energy deposition is greater and more complex than that associated with β-particles.

Absorbed dose

The energy absorbed per unit mass of tissue.

Gy

Abbreviation for the SI unit (gray) for radiation dose (1 Gy= 1 J kg−1). It is the absorbed dose per unit mass of tissue. The corresponding CGS unit is the rad (100 rad = 1 Gy). The rad is not recommended for use in the scientific literature.

Photons

A photon is a quantum of high-frequency electromagnetic radiation that is emitted spontaneously, either during a nuclear transformation (γ-rays) or as a result of orbital electron transitions (X-rays). In the context of radiation delivery, the energy or frequency of photons is sufficient to ionize atoms and lead to potential DNA damage.

X-rays

Photons emitted as a result of orbital electron transitions.

γ-Rays

Photons emitted during a nuclear transformation of a radionuclide.

keV

The abbreviation for a unit of energy (kiloelectronvolts) typically used to represent the energy associated with radionuclide emissions.

Auger electrons

Electrons ejected during suborbital transitions of an atom, typically following spontaneous nuclear transitions (radioactive decay).

Activities

A measure of radioactivity, typically in the unit of becquerel (Bq) or millicurie (mCi; the CGS unit). Radioactivity corresponds to the number of radionuclide transformations per unit time.

Theranostic

The general concept of using a radionuclide-labelled agent that may be imaged to guide radiopharmaceutical therapy; a radionuclide that may be used for both imaging and therapy.

Time-versus-activity curves

The amount of radioactivity in a particular region of the body as a function of time. Time-versus-activity curves are used in absorbed dose calculations; they may be obtained from imaging or direct sampling (for example, urine or serial biopsy or from animal studies).

Radionuclide transformations

The nuclear or atomic transformations associated with radioactive decay; the term ‘radionuclide disintegrations’ is also used.

Radiohalogen

Radioactive element in group 17 of the periodic table.

Radiosynovectomy

A treatment for arthritis or, more generally, inflammation that involves injection of radioactivity, typically as colloidal particles into the synovial cavity.

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Sgouros, G., Bodei, L., McDevitt, M.R. et al. Radiopharmaceutical therapy in cancer: clinical advances and challenges. Nat Rev Drug Discov 19, 589–608 (2020). https://doi.org/10.1038/s41573-020-0073-9

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