By Jake Johnson – Ac-225 is a medical radionuclide that has attracted significant interest from the oncology community since landmark studies in 2016 demonstrated its in-vivo efficacy in terminal stage metastatic resistant prostate cancer patients. Even before, it was considered a strong candidate for use in targeted alpha therapy of metastatic and distributed cancers. The Ac-225 decay chain has several features making it appropriate for this therapy modality. Not least is the emission of four successive alpha particles, with an energy totalling 28 MeV, meaning there is potential for very high targeted dose per unit activity of Ac-225. Furthermore, its 9.92-day half-life means that it can be produced, separated, and shipped while suffering minimal decay losses, in contrast to shorter lived candidate isotopes for targeted alpha therapy (TAT). This half-life is also well matched to the biological half-life of large targeting vectors such as antibodies, that have high specificity to cell membrane antigens. With respect to radiopharmaceutical synthesis, it has been demonstrated that Ac-225 can be conjugated to targeting molecules using typical chelators including Macropa and DOTA as well as novel macrocyclic chelators such as crown. Aside from these features, Ac-225 can be used as a generator for Bi-213, a TAT candidate itself that can be conjugated to smaller targeting molecules such as peptides or hormone analogues for targeting of different receptors and therefore cancer types.
There is currently a surge in Ac-225 research, including several clinical trials to develop good manufacturing protocols for Ac-based pharmaceuticals. The success of such research programmes relies on a stable and reliable supply of medical-grade Ac-225, which is currently a major issue. Medical Ac-225 can currently only be sourced from Th-229 generators in Oak Ridge National Laboratory (USA), or the Joint Research Centre of the European Commission in Karlsruhe (Germany) whose combined output is limited to approximately 70GBq per year. Research partnerships between accelerator complexes in North America with the capacity to produce Ac-225 through high energy proton irradiation of thorium, and radiopharmaceuticals start-up companies are being developed. Furthermore, accelerator-production of Ac-225 for medical purposes is being pursued in Europe by notably start-up companies such as alfaRim and PANTERA. However, there is no clear time scale on these developments.
Within the PRISMAP consortium, CERN MEDICIS has recently demonstrated that it is able to contribute towards Ac-225 research through the production of isotopically pure samples following the proton irradiation of ThO2. By using the technique of resonant laser ionisation and mass separation, it has been demonstrated that Ac-225 can be collected with an efficiency of greater than 10%, while suppressing the Ac-227 content that normally contaminates Ac-225 samples produced from irradiated targets to levels well below the exemption limit per patient dose. The separation efficiency has been measured during dedicated experiments and benchmarked using a combination of decay spectroscopy approaches at KU Leuven. Meanwhile the purity, most notably with respect to the Ac-227 activity in a Ac-225 sample from an irradiated ThO2 target was determined by the sensitive method of alpha-recoil spectroscopy. The production and separation of Ac-225 at CERN MEDICIS is under ongoing investigation to try to even further improve the efficiency of the technique, such that this novel radioisotope can be reliably delivered to partners for pre-clinical research.
You can find our recent publication on the topic on the Outcomes page of the PRISMAP website.