1Nuclear Science and Technology Research Institute (NSTRI), Tehran, Iran
2Radioisotope Products and Radiation Technology Section, Department of Nuclear Sciences and Applications, International Atomic Energy Agency (IAEA), Vienna, Austria
Introduction:Holmium-166 radionuclide is one of the most effective radionuclides used for targeted therapy with theranostic properties. One method to produce this radioisotope is via the decay of its parent (indirect method). In this study applicability of extraction chromatography (EXC) for separation of no carrier added 166Ho from neutron-irradiated natural dysprosium target followed by quality control procedures have been demonstrated. Methods:166Dy was produced by thermal neutron bombardment (5×1013n/cm2.s) of natural 164Dy target through 164Dy (n,γ) 165Dy (n,γ) 166Dy process in a nuclear reactor. The generator-produced 166Ho was separated from 166Dy by extraction chromatographic method. The extractant used in resin was 2-ethylhexyl 2-ethylhexylphosphonic acid (HEH[EHP]). The final solution went through radionuclide, chemical and radiochemical purity tests. Results: Using 1.5 M HNO3 as eluent at 25 °C, and flow rate of 1.5 mL/min, quantitative separation between Ho and Dy was achieved using LN2 resin in 1.5 h to yield in no carrier added 166HoCl3 (radionuclide purity >99.9%; separation yield; 76% and radiochemical purity >99% ITLC).
Conclusion: High specific activity 166HoCl3 produced in this study is highly suitable for metal sensitive labeling of monoclonal antibodies, fragments and especially peptides to yield efficient therapeutic doses for human applications.
Firestone RB, Shirley VS, Lawrence Berkeley Laboratory. Table of isotopes, 8E. CD-ROM. John Wiley & Sons, Inc. http://www.wiley.com/legacy/products/subject/physics/toi/
Bagheri R, Jalilian AR, Bahrami-Samani A, Mazidi M, Ghannadi-Maragheh M. Production of Holmium-166 DOTMP: A promising agent for bone marrow ablation in hematologic malignancies. Iran J Nucl Med. 2011;19(1):12-20.
Fakhari A, Jalilian A R, Yousefnia H, Bahrami Samani A, Akbari MR, Johari Deha F, Shafiee-Ardestani M, Khalaj A. Production, quality control, biodistribution assessment and preliminary dose evaluation of 166Ho-alendronate as a bone marrow ablative agent. Radiochim Acta. 2015;103(11):789-797.
Yousefnia H, Zolghadri S, Jalilian AR, Tajik M, Ghannadi-Maragheh M. Preliminary dosimetric evaluation of (166)Ho-TTHMP for human based on biodistribution data in rats. Appl Radiat Isot. 2014 Dec;94:260-5.
Khorami-Moghadam A, Bolouri B, Jalilian AR, Bahrami-Samani NM, Mazidi SM, Alirezapour B. Preclinical evaluation of holmium-166 labeled anti-VEGF-A(Bevacizumab). J Labelled Comp Radiopharm. 2013 Jun 30;56(8):365-9.
Gholipour N, Jalilian AR, Fazaeli Y, Sabzevari O, Moradkhani S, Bolourinovin F, Khalaj A. Development of [62Zn/62Cu]-DOTA-rituximab as a possible novel in vivo PET generator for anti-CD20 antigen imaging. Radiochim Acta. 2014;102(11):1035–1045.
Horwitz EP, McAlister DR, Bond AH, Barrans RE, Williamson JM. A process for the separation of 177Lu from neutron irradiated 176Yb targets. Appl Radiat Isot. 2005 Jul;63(1):23-36.
Knapp Jr FF. Reactor-produced therapeutic radionuclides. In: Knapp Jr FF, Dash A. Radiopharmaceuticals for therapy. Springer; 2016. p. 71-113.
Smith HL, Hoffman DC. Ion-exchange separations of the lanthanides and actinides by elution with ammonium alpha-hydroxy-isobutyrate. J Inorg Nucl Chem. 1956 Oct;3(3-4):243-7.
Choppin GR, Chopoorian JA. Complexes of the lanthanide elements with α-hydroxy carboxylate ligands. J Inorg Nucl Chem. 1961 Dec; 22(1-2):97-113.
Yoshida K, Haraguchi H. Determination of rare earth elements by liquid chromatography/inductively coupled plasma atomic emission. Anal Chem. 1984 Nov;56(13):2580-5.
Barkley DJ, Blanchette M, Cassidy RM, Elchuk S. Dynamic chromatographic systems for the determination of rare earths and thorium in samples from uranium ore refining processes. Anal chem. 1986 Sep;58(11):2222-6.
Mirzadeh, S. ORNL Nuclear Medicine Program Progress Report. ORNL/TM-12159. 1992; 6-11.
Sochacka RJ, Siekierski S. Reversed-phase partition chromatography with di-(2-ethylhexyl) orthophosphoric acid as the stationary phase: Part I. Separation of rare earths. J Chromatogr. 1964 Nov;16:376-84.
Aitzetmüller K, Buchtela K, Grass F, Hecht F. Electrophoresis of rare earth elements on cellulose acetate. Mikrochim Acta. 1966;(6):1101-13.
Chen M, Cassidy RM. Bonded-phase capillaries and the separation of inorganic ions by high-voltage capillary electrophoresis. J Chromatogr A. 1992 Jun 5;602(1-2):227-34.
Tang J, Wai CM. Solvent extraction of lanthanides with a crown ether carboxylic acid Anal Chem. 1986 Dec;58(14):3233-5.
Stevenson PC, Nervik WE. The radiochemistry of the rare earths: scandium, yttrium, and actinium. Washington: National Academies; 1961.
Dadachova E, Mirzadeh S, Lambrecht RM, Hetherington EL, Knapp Jr FF. Separation of carrier-free holmium-166 from neutron-irradiated dysprosium targets. Anal Chem. 1994 Dec;66(23):4272-7.
Nayak D, Lahiri S, Ramaswami A, Manohor SB. Separation of carrier-free holmium and dysprosium produced in 70 MeV 11 B 5+ irradiated europium target by liquid-Liquid extraction with HDEHP. Indian J Chem. 2000;39(10):1061-1065.
Lahiri S, Volkers KJ, Wierczinski B. Production of 166Ho through 164Dy(n, gamma)165Dy(n, gamma)166Dy(beta-)166Ho and separation of 166Ho. Appl Radiat Isot. 2004 Dec;61(6):1157-61.
Horwitz EP, Bloomquist CA. Chemical separations for super-heavy element searches in irradiated uranium targets. J Inorg Nucl Chem. 1975;37(2):425-34.