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Alpha Particle–Emitting Radiopharmaceuticals as Cancer Therapy: Biological Basis, Current Status, and Future Outlook for Therapeutics Discovery

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Abstract

Critical advances in radionuclide therapy have led to encouraging new options for cancer treatment through the pairing of clinically useful radiation-emitting radionuclides and innovative pharmaceutical discovery. Of the various subatomic particles used in therapeutic radiopharmaceuticals, alpha (α) particles show great promise owing to their relatively large size, delivered energy, finite pathlength, and resulting ionization density. This review discusses the therapeutic benefits of α-emitting radiopharmaceuticals and their pairing with appropriate diagnostics, resulting in innovative “theranostic” platforms. Herein, the current landscape of α particle-emitting radionuclides is described with an emphasis on their use in theranostic development for cancer treatment. Commonly studied radionuclides are introduced and recent efforts towards their production for research and clinical use are described. The growing popularity of these radionuclides is explained through summarizing the biological effects of α radiation on cancer cells, which include DNA damage, activation of discrete cell death programs, and downstream immune responses. Examples of efficient α-theranostic design are described with an emphasis on strategies that lead to cellular internalization and the targeting of proteins involved in therapeutic resistance. Historical barriers to the clinical deployment of α-theranostic radiopharmaceuticals are also discussed. Recent progress towards addressing these challenges is presented along with examples of incorporating α-particle therapy in pharmaceutical platforms that can be easily converted into diagnostic counterparts.

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Acknowledgements

H.C.M. is a CPRIT Scholar of Cancer Research. The authors also thank Kelly Kage of the University of Texas MD Anderson Cancer Center Division of Diagnostic Imaging for providing the illustration used in Fig. 1 and Christine F. Wogan of the University of Texas MD Anderson Cancer Center Division of Radiation Oncology for editing the manuscript.

Funding

R.P.C., D.K.G., and H.C.M. acknowledge the Cancer Prevention and Research Institute of Texas (CPRIT) for financial support. G.O.S. and S.J.B. acknowledge the University of Texas MD Anderson Cancer Center, Division of Radiation Oncology for financial support. S.J.B. acknowledges the American Association of Physicists in Medicine for financial support. G.O.S. acknowledges the National Institutes of Health, Department of Defense, Alpha Tau Medical, Artios Pharma, and Convergent Radiotherapy and Radiosurgery (CRnR) for financial support. This work was also supported in part by Cancer Center Support (Core) Grant P30 from the National Cancer Institute, National Institutes of Health to The University of Texas MD Anderson Cancer Center (PI: PW Pisters).

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Authors and Affiliations

  1. Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, 1881 East Rd, Houston, TX, 77054, USA

    Ryan P. Coll, Dimitra K. Georgiou & H. Charles Manning

  2. Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Blvd, Houston, TX, 77030, USA

    Scott J. Bright, David K.J. Martinus & Gabriel O. Sawakuchi

  3. Cyclotron Radiochemistry Facility, The University of Texas MD Anderson Cancer Center, 1881 East Rd, Houston, TX, 77054, USA

    H. Charles Manning

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R.P.C., S.J.B., D.K.J.M., A.S.C., D.K.G., G.O.S., and H.C.M. contributed to the design, background research, and writing of this manuscript.

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Correspondence to H. Charles Manning.

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G.O.S. has research agreements with Alpha Tau Medical, Artios Pharma and Convergent Radiotherapy and Radiosurgery.

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Coll, R.P., Bright, S.J., Martinus, D.K. et al. Alpha Particle–Emitting Radiopharmaceuticals as Cancer Therapy: Biological Basis, Current Status, and Future Outlook for Therapeutics Discovery. Mol Imaging Biol 25, 991–1019 (2023). https://doi.org/10.1007/s11307-023-01857-y

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