Aleksandr Vasiliev

A method for large-scale production of prospective medical radionuclide ²²⁵Ac including irradiation of a massive metallic ²³²Th-target in Nb-shell with 160 MeV-protons and original procedure of highly purified ²²⁵Ac isolation has been developed.

Introduction: The feasibility of preparing the “in-house” generators and the Th- DTPA(DOTA)-Nimotuzumab radioimmunoconjugate was evaluated. 226Th is perspective for TAT, however, due to short half-life it is preferable to apply this radionuclide for readily available epithelial malignancies. Nimotuzumab being specific for EGFR expressing cells as a targeting moiety is considered to be suitable for thorium delivery. Methods: TEVA extraction chromatographic resin and anion exchange resin AG 1x8 were used as sorbents for 226Th generator. In order to determine features of labeling by Th4+ we applied 234Th as a longer-lived analog of short-lived 226Th and the immunoconjugates DTPA(DOTA)-Nimotuzumab were used for radiolabeling. Results: The generator on the base of TEVA resin has shown higher volume activity of the product compared to the AG 1x8. The 226Th volume concentration was up to 80%/mL. The radiolabeling of BFCA by thorium radioisotopes reached 95% at the MR(Th:p-SCN-Bn-DTPA) = 1:100 and 86% for MR(Th:p-SCN-Bn-DOTA) = 1:5000 at 90°C. The procedure of Nimotuzumab labeling with Th4+ for radiotherapy of EGFR-overexpressing carcinomas was established. The overall labeling yield in both radioimmunoconjugates - DTPA and DOTA functionalized - was in the range of 45-50%. The immunoconjugate Nimotuzumab-p-SCN-Bn-DTPA was obtained with a molar ratio 1:25 (Nimotuzumab: BFCA), within 1 hour of conjugation at 25¹C and labelled via postconjugation approach. Whereas Nimotuzumab-p-SCN-Bn-DOTA was obtained at the same conditions, but radiolabeled by the method of pre-conjugation. Conclusion: Thorium-234 incorporation into both radioimmunoconjugates reached 45-50%. It has been shown that Th-DTPA-Nimotuzumab radioimmunoconjugate specifically bound with EGFR overexpressing epidermoid carcinoma A431 cells.

A radionuclide generator of the short-lived alpha emitter ²²⁶Th was proposed. An original scheme consisting of two in-series chromatographic columns was developed for rapidly producing a neutral citric-buffered eluate of high purity ²²⁶Th. The first column filled with TEVA resin retained the parent ²³⁰U, while ²²⁶Th was eluted with 7 M HCl solution to be immediately adsorbed on the second column containing DGA resin or UTEVA resin. Having substituted the strongly acidic medium of second column with neutral salt solution, ²²⁶Th was desorbed with diluted citric buffer solution. One cycle of generator milking took 5–7 min and produced >90% of ²²⁶Th in 1.5 mL of eluate (pH 4.5–5.0) appropriate for direct use in radiopharmaceutical synthesis. The ²³⁰U impurity in ²²⁶Th eluate was less than 0.01%. The proposed two-column ²³⁰U/²²⁶Th generator was tested over 2 months including a second loading of ²³⁰U additionally accumulated from ²³⁰Pa.

A unique two-column ²³⁰U/²²⁶Th generator has been developed. The focus was hold on obtaining ²²⁶Th of high purity in a solution amenable to further labeling. The first column of the proposed generator filled with TEVA Resin held ²³⁰U, from which ²²⁶Th was eluted with 7 M HCl solution. UTEVA Resin pretreated with nitric acid solution was used as a sorbent for the second column for thorium retention. ²²⁶Th was extracted with 0.01-0.05 M citric buffer solution. One cycle of generator milking took 5-7 minutes and produced > 90% of ²²⁶Th in 1.5 ml of eluate, pH 4.5-5.0. The proposed two-column ²³⁰U/²²⁶Th generator was tested over two months including a second loading of ²³⁰U additionally accumulated from ²³⁰Pa. The ²³⁰U impurity in ²²⁶Th eluate was less than 0.01% allowing to use it directly in synthesis of radiopharmaceutical compounds.

Liquid–liquid extraction of protactinium with different extractants (1-octanol, MIBK, aliquat 336) was studied depending on concentration of nitric and hydrochloric acids, presence of bulk amount of thorium, fluoride ions, and addition of boric acid or Al³⁺ ions as a masking agent. The extraction with 1-octanol followed by back-extraction with 7 M HCl + 0.1 M HF solution proved to be appropriate for selective ²³⁰Pa isolation from thorium irradiated with medium-energy protons. The proposed procedure provided simultaneous production of medical ²²⁵Ac and ²³⁰Pa/²³⁰U from the same Th-target. The experimental cross-sections of ²³⁰Pa formation in the reaction ²³²Th(p,3n)²³⁰Pa were determined for the protons energy range of 140–35 MeV and compared with literature data. The yield of ²³⁰U and impurities of ²³²U and ²³³U depending on the energy of protons entering a thick thorium target were estimated.

A new two-column ²²⁵Ac/²¹³Bi generator was developed specifically for using ²²⁵Ac containing an impurity of long lived ²²⁷Ac. The parent ²²⁵Ac was retained on the first Actinide Resin column, while ²¹³Bi was accumulated on the second column filled with AG MP-50 resin via continuous elution and decay of intermediate ²²¹Fr. The ²¹³Bi accumulation was realized in circulation mode which allowed a compact generator design. It was demonstrated that ²¹³Bi could be quickly and effectively extracted from AG MP-50 in form of complexes with various chelating agents including DTPA and DOTA. The performance of the generator presented and a conventional single-column generator on the base of AG MP-50 was tested and both generators were loaded with ²²⁵Ac containing ²²⁷Ac impurity. The ²¹³Bi generation efficiencies were comparable and greater than 70%, whereas the developed generator provided a deeper degree of purification of ²¹³Bi from Ac isotopes and decay products of ²²⁷Ac.

The radiation resistance of sorbents AG 50 W-X8, Ac resin, and UTEVA resin in contact with hydrochloric solutions under irradiation with 10 MeV electrons in a wide absorbed-dose range up to 2 MGy was studied. Mass distribution ratios and total sorption capacity were used as quantitative measures to determine the changes in ion exchange or extractive abilities of the resins. Based on the data obtained and on a review of the performance of the ²²⁵Ac/²¹³Bi generators reported in the literature, the applicability of investigated resins for high activity loaded onto different generator systems was concluded.