Targeted alpha-particle therapy

Targeted alpha-particle therapy (or TAT) is an in-development method of targeted radionuclide therapy of various cancers. It employs radioactive substances which undergo alpha decay to treat diseased tissue at close proximity.[1] It has the potential to provide highly targeted treatment, especially to microscopic tumour cells. Targets include leukemias, lymphomas, gliomas, melanoma, and peritoneal carcinomatosis.[2] As in diagnostic nuclear medicine, appropriate radionuclides can be chemically bound to a targeting biomolecule which carries the combined radiopharmaceutical to a specific treatment point.[3]

It has been said that "α-emitters are indispensable with regard to optimisation of strategies for tumour therapy".[4]

Advantages of alpha emitters
Comparison of range of α (red) and β− (white) particles

The primary advantage of alpha particle (α) emitters over other types of radioactive sources is their very high linear energy transfer (LET) and relative biological effectiveness (RBE).[5] Beta particle (β) emitters such as yttrium-90 can travel considerable distances beyond the immediate tissue before depositing their energy, while alpha particles deposit their energy in 70–100 μm long tracks.[6]

Alpha particles are more likely than other types of radiation to cause double-strand breaks to DNA molecules, which is one of several effective causes of cell death.[7][8]

Production

Some α emitting isotopes such as 225Ac and 213Bi are only available in limited quantities from 229Th decay, although cyclotron production is feasible.[9][10][11]

The ARRONAX cyclotron can produce 211At by irradiation of 209Bi.[12][9]

Applications

Though many α-emitters exist, useful isotopes would have a sufficient energy to cause damage to cancer cells, and a half-life that is long enough to provide a therapeutic dose without remaining long enough to damage healthy tissue.

Immunotherapy

Several radionuclides have been studied for use in immunotherapy. Though β-emitters are more popular, in part due to their availability, trials have taken place involving 225Ac, 211At, 212Pb and 213Bi.[9]

Peritoneal carcinomas

Treatment of peritoneal carcinomas has promising early results limited by availability of α-emitters compared to β-emitters.[4]

Bone metastases

223Ra was the first α-emitter approved by the FDA in the United States for treatment of bone metastases from prostate cancer, and is a recommended treatment in the UK by NICE.[3][13] In a phase III trial comparing 223Ra to a placebo, survival was significantly improved.[14]

Leukaemia

Early trials of 225Ac and 213Bi have shown evidence of anti-tumour activity in Leukaemia patients.[15]

Melanomas

Phase I trials on melanomas have shown 213Bi is effective in causing tumour regression.[16][17]

Solid tumours

The short path length of alpha particles in tissue, which makes them well suited to treatment of the above types of disease, is a negative when it comes to treatment of larger bodies of solid tumour by intravenous injection.[18][19] However, potential methods to solve this problem of delivery exist, such as direct intratumoral injection[20] and anti-angiogenic drugs.[21][3] Limited treatment experience of low grade malignant gliomas has shown possible efficacy.[22]

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See also

References
  1. Committee on State of the Science of Nuclear Medicine; National Research Council; Division on Earth and Life Studies; Institute of Medicine; Nuclear and Radiation Studies Board; Board on Health Sciences Policy (2007). "Targeted Radionuclide Therapy". Advancing nuclear medicine through innovation. Washington, D.C.: National Academies Press. doi:10.17226/11985. ISBN 978-0-309-11067-9. PMID 20669430.
  2. Mulford, DA; Scheinberg, DA; Jurcic, JG (January 2005). "The promise of targeted {alpha}-particle therapy". Journal of Nuclear Medicine. 46 Suppl 1: 199S–204S. PMID 15653670.
  3. Dekempeneer, Yana; Keyaerts, Marleen; Krasniqi, Ahmet; Puttemans, Janik; Muyldermans, Serge; Lahoutte, Tony; D’huyvetter, Matthias; Devoogdt, Nick (19 May 2016). "Targeted alpha therapy using short-lived alpha-particles and the promise of nanobodies as targeting vehicle". Expert Opinion on Biological Therapy. 16 (8): 1035–1047. doi:10.1080/14712598.2016.1185412. PMC 4940885. PMID 27145158.
  4. Seidl, Christof; Senekowitsch-Schmidtke, Reingard (2011). "Targeted Alpha Particle Therapy of Peritoneal Carcinomas". In Baum, Richard P. (ed.). Therapeutic nuclear medicine. Berlin: Springer. pp. 557–567. doi:10.1007/174_2012_678. ISBN 978-3-540-36718-5.
  5. Kane, Suzanne Amador (2003). Introduction to physics in modern medicine (Repr. ed.). London: Taylor & Francis. p. 243. ISBN 9780415299633.
  6. Elgqvist, Jörgen; Frost, Sofia; Pouget, Jean-Pierre; Albertsson, Per (2014). "The Potential and Hurdles of Targeted Alpha Therapy – Clinical Trials and Beyond". Frontiers in Oncology. 3: 324. doi:10.3389/fonc.2013.00324. PMC 3890691. PMID 24459634.
  7. Baum, Richard P (2014). Therapeutic Nuclear Medicine. Heidelberg: Springer. p. 98. ISBN 9783540367192.
  8. Hodgkins, Paul S.; O'Neill, Peter; Stevens, David; Fairman, Micaela P. (December 1996). "The Severity of Alpha-Particle-Induced DNA Damage Is Revealed by Exposure to Cell-Free Extracts". Radiation Research. 146 (6): 660–7. Bibcode:1996RadR..146..660H. doi:10.2307/3579382. JSTOR 3579382. PMID 8955716.
  9. Seidl, Christof (April 2014). "Radioimmunotherapy with α-particle-emitting radionuclides". Immunotherapy. 6 (4): 431–458. doi:10.2217/imt.14.16. PMID 24815783.
  10. Apostolidis, C.; Molinet, R.; McGinley, J.; Abbas, K.; Möllenbeck, J.; Morgenstern, A. (March 2005). "Cyclotron production of Ac-225 for targeted alpha therapy". Applied Radiation and Isotopes. 62 (3): 383–387. doi:10.1016/j.apradiso.2004.06.013. PMID 15607913.
  11. Miederer, Matthias; Scheinberg, David A.; McDevitt, Michael R. (September 2008). "Realizing the potential of the Actinium-225 radionuclide generator in targeted alpha particle therapy applications". Advanced Drug Delivery Reviews. 60 (12): 1371–1382. doi:10.1016/j.addr.2008.04.009. PMC 3630456. PMID 18514364.
  12. Haddad, Ferid; Barbet, Jacques; Chatal, Jean-Francois (1 July 2011). "The ARRONAX Project". Current Radiopharmaceuticals. 4 (3): 186–196. doi:10.2174/1874471011104030186. PMID 22201708.
  13. "Radium-223 dichloride for treating hormone-relapsed prostate cancer with bone metastases". National Institute for Health and Care Excellence. Retrieved 19 December 2016.
  14. Parker, C.; Nilsson, S.; Heinrich, D.; Helle, S.I.; O'Sullivan, J.M.; Fosså, S.D.; Chodacki, A.; Wiechno, P.; Logue, J.; Seke, M.; Widmark, A.; Johannessen, D.C.; Hoskin, P.; Bottomley, D.; James, N.D.; Solberg, A.; Syndikus, I.; Kliment, J.; Wedel, S.; Boehmer, S.; Dall'Oglio, M.; Franzén, L.; Coleman, R.; Vogelzang, N.J.; O'Bryan-Tear, C.G.; Staudacher, K.; Garcia-Vargas, J.; Shan, M.; Bruland, Ø.S.; Sartor, O. (18 July 2013). "Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer". New England Journal of Medicine. 369 (3): 213–223. doi:10.1056/NEJMoa1213755. PMID 23863050.
  15. Jurcic, Joseph G.; Rosenblat, Todd L. (2014). "Targeted Alpha-Particle Immunotherapy for Acute Myeloid Leukemia". American Society of Clinical Oncology Educational Book. 34: e126–e131. doi:10.14694/EdBook_AM.2014.34.e126. PMID 24857092.
  16. Allen, Barry J; Raja, Chand; Rizvi, Syed; Li, Yong; Tsui, Wendy; Zhang, David; Song, Emma; Qu, Chang Fa; Kearsley, John; Graham, Peter; Thompson, John (21 August 2004). "Targeted alpha therapy for cancer". Physics in Medicine and Biology. 49 (16): 3703–3712. Bibcode:2004PMB....49.3703A. doi:10.1088/0031-9155/49/16/016. PMID 15446799.
  17. Kim, Young-Seung; Brechbiel, Martin W. (6 December 2011). "An overview of targeted alpha therapy". Tumor Biology. 33 (3): 573–590. doi:10.1007/s13277-011-0286-y. PMID 22143940.
  18. Larson, Steven M.; Carrasquillo, Jorge A.; Cheung, Nai-Kong V.; Press, Oliver W. (22 May 2015). "Radioimmunotherapy of human tumours". Nature Reviews Cancer. 15 (6): 347–360. doi:10.1038/nrc3925. PMC 4798425. PMID 25998714.
  19. Sofou, S (2008). "Radionuclide carriers for targeting of cancer". International Journal of Nanomedicine. 3 (2): 181–99. doi:10.2147/ijn.s2736. PMC 2527672. PMID 18686778.
  20. Arazi, L; Cooks, T; Schmidt, M; Keisari, Y; Kelson, I (21 August 2007). "Treatment of solid tumors by interstitial release of recoiling short-lived alpha emitters". Physics in Medicine and Biology. 52 (16): 5025–5042. Bibcode:2007PMB....52.5025A. doi:10.1088/0031-9155/52/16/021. PMID 17671351.
  21. Huang, Chen-Yu; Pourgholami, Mohammad H.; Allen, Barry J. (November 2012). "Optimizing radioimmunoconjugate delivery in the treatment of solid tumor". Cancer Treatment Reviews. 38 (7): 854–860. doi:10.1016/j.ctrv.2011.12.005. PMID 22226242.
  22. Cordier, Dominik; Krolicki, Leszek; Morgenstern, Alfred; Merlo, Adrian (May 2016). "Targeted Radiolabeled Compounds in Glioma Therapy". Seminars in Nuclear Medicine. 46 (3): 243–249. doi:10.1053/j.semnuclmed.2016.01.009.
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