Abstract
α-Emitting radionuclides have radiobiological properties that make them particularly attractive for the therapy of a number of difficult-to-treat diseases—such as cancers that are blood-borne or disseminated throughout the body—as well as residual cancer remaining after surgery. While there are many α-emitting radionuclides in nature, only ten have been identified as potentially useful for medical applications. And unfortunately, most of the members of this useful subset are difficult to obtain or are very expensive to produce. Despite these limitations, however, the enticing prospect of using these radionuclides to address medically unmet needs has prompted efforts to attach them to disease-targeting vectors and test their therapeutic efficacy in animal models of disease. Both metallic and non-metallic α-emitting radionuclides have been explored for targeted therapy, and as such, a variety of approaches to incorporating these radionuclides into targeting vectors have been developed, including direct covalent modification and the use of bifunctional chelators. While a fair number of bifunctional chelators have been developed, only a handful—e.g. CHX-A″-DTPA, DOTA, and HOPO—can be used for both α-emitters and radionuclides with imaging properties. In contrast, one of the α-emitting radionuclides that is not readily chelated, 211At, can be attached to disease-targeting agents through efficient electrophilic aromatic substitution reactions using trialkylstannyl intermediates or direct labeling on aromatic boron cage moieties. Radiopharmaceuticals containing α-emitting radionuclides are undergoing preclinical investigations for treatment of a number of cancers as well as the treatment of drug-resistant bacterial and viral infections. Furthermore, an α-emitting radiopharmaceutical—223RaCl2 (Xofigo™; Bayer HealthCare Pharmaceuticals, Inc., Whippany NJ, USA)—is an FDA-approved product, and several other radiopharmaceuticals containing α-emitting radionuclides have progressed to clinical trials.
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References
Vaidyanathan G, Zalutsky MR. Targeted therapy using alpha emitters. Phys Med Biol. 1996;41(10):1915–31.
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.
Brechbiel MW. Targeted alpha-therapy: past, present, future? Dalton Trans. 2007;43:4918–28.
Mulford DA, Scheinberg DA, Jurcic JG. The promise of targeted alpha-particle therapy. J Nucl Med. 2005;46(Suppl 1):199S–204S.
Couturier O, Supiot S, Degraef-Mougin M, Faivre-Chauvet A, Carlier T, Chatal JF, et al. Cancer radioimmunotherapy with alpha-emitting nuclides. Eur J Nucl Med Mol Imaging. 2005;32(5):601–14.
Wadas TJ, Pandya DN, Sai KKS, Mintz A. Molecular targeted alpha-particle therapy for oncologic applications. Am J Roentgenol. 2014;203(2):253–60.
Cleaves MA. Radium: with a preliminary note on radium rays in the treatment of cancer. Med Rec. 1903;64(16):601–6.
Newcomet WS. Internal administration of radium. In: Radium and radiotherapy: radium, thorium, and other radio-active elements in medicine and surgery. New York: Lea & Febiger; 1914. p. 97–105.
Simpson FE. Radium therapy. St. Louis: C.V. Mosby Company; 1922.
Clark C. Radium girls: women and industrial health reform 1910–1935. Chapel Hill: University of North Carolina Press; 1997.
Rowland RE. Radium in humans: a review of U.S. Studies. In: Do U, editor. Energy. Chicago: University of Chicago; 1994. p. 233.
Hall EJ, Giaccia AJ. Radiobiology for the radiologist. 6th ed. Philadelphia: Lippincott Williams and Wilkins; 2006.
Hall EJ, Giaccia AJ. Linear energy transfer and relative biologic effectiveness. Radiobiology for the radiologist. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2006.
Sgouros G. Alpha-particles for targeted therapy. Adv Drug Deliv Rev. 2008;60(12):1402–6.
Wilbur DS. Chemical and radiochemical considerations in radiolabeling with α-emitting radionuclides. Curr Radiopharm. 2011;4(3):214–47.
Muller C, Vermeulen C, Koster U, Johnston K, Turler A, Schibli R, et al. Alpha-PET with terbium-149: evidence and perspectives for radiotheragnostics. EJNMMI Radiopharm Chem. 2016:1–5.
de Kruijff RM, Wolterbeek HT, Denkova AG. A critical review of alpha radionuclide therapy-how to deal with recoiling daughters? Pharmaceuticals (Basel). 2015;8(2):321–36.
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(5):895–904.
Atcher RW, Friedman AM, Hines JJ. An improved generator for the production of 212Pb and 212Bi for 224Ra. Appl Radiat Isot. 1988;39:283–6.
Morgenstern A, Lebeda O, Stursa J, Bruchertseifer F, Capote R, McGinley J, et al. Production of 230U/226Th for targeted alpha therapy via proton irradiation of 231Pa. Anal Chem. 2008;80(22):8763–70.
Kulyukhin SA, Auerman LN, Novichenko VL, Mikheev NB, Rumer IA, Kamenskaya AN, et al. Production of microgram quantities of einsteinium-253 by reactor irradiation of californium. Inorg Chim Acta. 1985;110:25–6.
Zaitseva NG, Dmitriev SN, Maslov OD, Molokanova LG, Starodub GY, Shishkina TV, et al. Terbium-149 for nuclear medicine. The production of 149Tb via heavy ions induced nuclear reactions. Czechoslov J Phys. 2003;53:A455–A8.
Beyer G-J, Comar JJ, Dakovic M, Soloviev D, Tamburella C, Hagebo E, et al. Production routes of the alpha emitting 149Tb for medical application. Radiochim Acta. 2002;90:247–52.
Beyer GJ, Miederer M, Vranjes-Duric S, Comor JJ, Kunzi G, Hartley O, et al. Targeted alpha therapy in vivo: direct evidence for single cancer cell kill using 149Tb-rituximab. Eur J Nucl Med Mol Imaging. 2004;31(4):547–54.
Muller C, Vermeulen C, Koster U, Johnston K, Turler A, Schibli R, et al. Alpha-PET with terbium-149: evidence and perspectives for radiotheranostics. EJNMMI Radiopharm Chem. 2016;1:1–5.
Price EW, Orvig C. Matching chelators to radiometals for radiopharmaceuticals. Chem Soc Rev. 2014;43(1):260–90.
Brechbiel MW. Bifunctional chelates for metal nuclides. Q J Nucl Med Mol Imaging. 2008;52(2):166–73.
Hassfjell S, Brechbiel MW. The development of the a-particle emitting radionuclides 212Bi and 213Bi, and their decay chain related radionuclides, for therapeutic applications. Chem Rev. 2001;101(7):2019–36.
Corson DR, MacKenzie KR, Segre E. Artificially radioactive element 85. Phys Rev. 1940;58:672–8.
Hermann A, Hoffmann R, Ashcroft NW. Condensed astatine: monatomic and metallic. Phys Rev Lett. 2013;111(11):116404.
Pruszynski M, Bilewicz A, Zalutsky MR. Preparation of Rh[16aneS4-diol]211At and Ir[16aneS4-diol]211At complexes as potential precursors for astatine radiopharmaceuticals. Part I: synthesis. Bioconjug Chem. 2008;19(4):958–65.
Wilbur DS. Radiohalogenation of proteins: an overview of radionuclides, labeling methods, and reagents for conjugate labeling. Bioconjug Chem. 1992;3(6):433–70.
Wilbur DS. [211At]Astatine-labeled compound stability: issues with released [211at]astatide and development of labeling reagents to increase stability. Curr Radiopharm. 2008;1:144–76.
Wilbur DS, Chyan MK, Nakamae H, Chen Y, Hamlin DK, Santos EB, et al. Reagents for astatination of biomolecules. 6. An intact antibody conjugated with a maleimido-closo-decaborate(2-) reagent via sulfhydryl groups had considerably higher kidney concentrations than the same antibody conjugated with an isothiocyanato-closo-decaborate(2-) reagent via lysine amines. Bioconjug Chem. 2012;23(3):409–20.
McDevitt MR, Ma D, Simon J, Frank RK, Scheinberg DA. Design and synthesis of 225Ac radioimmunopharmaceuticals. Appl Radiat Isot. 2002;57(6):841–7.
Maguire WF, McDevitt MR, Smith-Jones PM, Scheinberg DA. Efficient 1-step radiolabeling of monoclonal antibodies to high specific activity with 225Ac for alpha-particle radioimmunotherapy of cancer. J Nucl Med. 2014;55(9):1492–8.
Deal KA, Davis IA, Mirzadeh S, Kennel SJ, Brechbiel MW. Improved in vivo stability of actinium-225 macrocyclic complexes. J Med Chem. 1999;42(15):2988–92.
Norenberg JP, Krenning BJ, Konings IRHM, Kusewitt DF, Nayak TK, Anderson TL, et al. 213Bi-[DOTA0, Tyr3]octreotide peptide receptor radionuclide therapy of pancreatic tumors in a preclinical animal model. Clin Cancer Res. 2006;12(3, Pt. 1):897–903.
Park SI, Shenoi J, Pagel JM, Hamlin DK, Wilbur DS, Orgun N, et al. Conventional and pretargeted radioimmunotherapy using bismuth-213 to target and treat non-Hodgkin lymphomas expressing CD20: a preclinical model toward optimal consolidation therapy to eradicate minimal residual disease. Blood. 2010;116(20):4231–9.
Kirby HW, Salutsky ML. The radiochemistry of radium, U.S. Atomic Energy Commission NAS-NS 3057. Springfield: National Academy of Sciences; 1964. p. 172.
Gott M, Steinbach J, Mamat C. The radiochemical and radiopharmaceutical applications of radium. Open Chem. 2016;14(1):118–29.
Rojas JV, Woodward JD, Chen N, Rondinone AJ, Castano CH, Mirzadeh S. Synthesis and characterization of lanthanum phosphate nanoparticles as carriers for Ra-223 and Ra-225 for targeted alpha therapy. Nucl Med Biol. 2015;42(7):614–20.
Muller C, Zhernosekov K, Koster U, Johnston K, Dorrer H, Hohn A, et al. A unique matched quadruplet of terbium radioisotopes for PET and SPECT and for alpha- and beta- radionuclide therapy: an in vivo proof-of-concept study with a new receptor-targeted folate derivative. J Nucl Med. 2012;53(12):1951–9.
Le Du A, Sabatie-Gogova A, Morgenstern A, Montavon G. Is DTPA a good competing chelating agent for Th(IV) in human serum and suitable in targeted alpha therapy? J Inorg Biochem. 2012;109:82–9.
Larsen RH, Borrebaek J, Dahle J, Melhus KB, Krogh C, Valan MH, et al. Preparation of TH227-labeled radioimmunoconjugates, assessment of serum stability and antigen binding ability. Cancer Biother Radiopharm. 2007;22(3):431–7.
Ramdahl T, Bonge-Hansen HT, Ryan OB, Larsen S, Herstad G, Sandberg M, et al. An efficient chelator for complexation of thorium-227. Bioorg Med Chem Lett. 2016;26(17):4318–21.
Deri MA, Ponnala S, Kozlowski P, Burton-Pye BP, Cicek HT, Hu C, et al. P-SCN-Bn-HOPO: a superior bifunctional chelator for 89Zr ImmunoPET. Bioconjug Chem. 2015;26(12):2579–91.
Yordanov AT, Garmestani K, Zhang M, Zhang Z, Yao Z, Phillips KE, et al. Preparation and in vivo evaluation of linkers for 211At labeling of humanized anti-Tac. Nucl Med Biol. 2001;28(7):845–56.
Lindegren S, Andersson H, Back T, Jacobsson L, Karlsson B, Skarnemark G. High-efficiency astatination of antibodies using N-iodosuccinimide as the oxidising agent in labelling of N-succinimidyl 3-(trimethylstannyl)benzoate. Nucl Med Biol. 2001;28(1):33–9.
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Wilbur, D.S. (2019). The Radiopharmaceutical Chemistry of Alpha-Emitting Radionuclides. In: Lewis, J., Windhorst, A., Zeglis, B. (eds) Radiopharmaceutical Chemistry. Springer, Cham. https://doi.org/10.1007/978-3-319-98947-1_23
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