Speaker
Description
Coupling alpha-emitting radionuclides with disease seeking targeting vectors for site-selective delivery of cytotoxic radiation has the potential to be a powerful technique for treating metastatic and hard to treat cancers. The success of this type of treatment, termed targeted alpha therapy (TAT), is reliant on the availability of isotope and ability to securely tether said isotope to a biomolecule of interest. With four alpha particles in its decay chain, actinium-225 (225Ac; t1/2 = 9.9 d) is a promising candidate isotope for TAT. Similarly, the single alpha-emitter lead-212 (212Pb; t1/2 = 10.6 h) has generated significant interest as a matched theranostic pair with 203Pb (t1/2 = 51.9 h), compatible with single-photon emission computed tomography (SPECT) imaging. The current limited global supply, and lack of appropriate chelating ligands (molecules used to bind the isotope to the biomolecule) has delayed the advancement of TAT-drugs towards the clinic.1 Herein, we describe efforts to produce, purify, and evaluate the radiolabeling ability of 225Ac and 212Pb, by leveraging TRIUMF’s unique infrastructure (located in Vancouver, Canada). For 225Ac, the ISAC isotope separation on-line (ISOL) facility, as well as the 500 MeV cyclotron were used to produce preclinical and clinical amounts of isotope, respectively. For 212Pb, a 228Th generator was manufactured.
225Ac alongside parent nuclide radium-225 (225Ra; t1/2 = 14.8 d) were produced via spallation of uranium carbide targets with 480 MeV protons on ISOL’s radioactive beam facility. Downstream from the target, a high-resolution mass separator was used to isolate 225Ra and 225Ac ions from other isotopes produced in the spallation process. Implantation resulted in isolation of 1.0 – 7.5 and 1.4 – 18.0 MBq of 225Ra and 225Ac, respectively. The implanted activity was etched off the sample stage with dilute acid, and 225Ac was separated in >99% yield from 225Ra using solid phase extraction (DGA resin).2 This method has resulted in the isolation of MBq quantities of both 225Ra and 225Ac, where the former can be stored and used as a generator for 225Ac. Clinical scale-production via irradiation of 232Th targets on the 500 MeV cyclotron resulted in 225Ac products suitable for our studies. Conveniently, the by-products produced during spallation can be extracted to prepare a 228Th/212Pb generator that can deliver up to 9 – 10 MBq of 212Pb daily.3 Subsequently, 225Ac and 212Pb coordination properties with a library of chelating ligands along with commercial standard DOTA were evaluated by testing radiolabeling efficiency, and complex stability.
In conclusion, we have successfully established a production method for 225Ac which yields activities adequate for pre-clinical screening (225Ac via ISOL, or 212Pb via 232Th spallation) or clinical production (225Ac via 232Th spallation). Furthermore, several novel radiometal-chelators showed promising radiolabeling properties and kinetic inertness in vitro compared to commercial standards and will be tested in vivo in future studies.
(1) Robertson, A. K. H. et al. Curr. Radiopharm. 2018, 11 (3), 156–172. https://doi.org/10.2174/1874471011666180416161908.
(2) Ramogida, C. F.; et al. EJNMMI Radiopharm. Chem. 2019, 4 (1), 21. https://doi.org/10.1186/s41181-019-0072-5.
(3) McNeil, B. L.; et al. EJNMMI Radiopharm. Chem. 2021, 6 (1), 6. https://doi.org/10.1186/s41181-021-00121-4.
