Production of Actinium-225 at the Canadian Nuclear Laboratories: Operation of a Thorium Generator and Quality Control of Ac-225

Objectives: Targeted Alpha Therapy (TAT) has demonstrated considerable promise in the treatment of a range of cancers in both preclinical and more recently clinical research. In particular, work with the alpha-emitting radionuclide ²²⁵Ac has been effectively employed in a clinical setting due to the relatively rapid decay cascade that leads to 4 alpha and 2 beta emissions. One limitation for TAT has been caused by access to the vital radionuclide. Traditionally, ²²⁵Ac has been sourced from thorium/actinium generators based on the alpha decay of stockpiles of ²²⁹Th. ²²⁹Th is itself the alpha-decay product from ²³³U. Due to proliferation issues associated with ²³³U, until recently only three thorium/actinium generators have been reported in the literature. Described here is the construction and operation of a thorium/actinium radionuclide generator, at the Canadian Nuclear Laboratories (CNL), capable of supporting preclinical and limited clinical research in the area of TAT.

Methods: Thorium was recovered and purified by a combination of anion exchange and extraction chromatography from aged ²³³U stockpiles at CNL. Initially, the isolation of thorium from the parent uranium fraction was accomplished using standard anion exchange chromatography, however, improved separations were found by employing tetraalkyldiglycolamide (DGA) extraction chromatography resins. Using this material, two distinct generators have been constructed, allowing for alternating monthly milkings yielding pure fractions of both ²²⁵Ac and its parent radionuclide ²²⁵Ra. The milking process has been automated to allow for remote handling and improved material quality. A separation scheme for ²²⁵Ra and ²²⁵Ac has been developed, based upon the composition of the thorium generator employing a combination of anion exchange and DGA and TEVA extraction chromatography resins. Quality Control parameters for have been developed for purified ²²⁵Ac using ICP-MS, gamma and alpha spectroscopy. In addition, test labeling of simple chelates has been introduced as a product release criterion.

Results: The ²³³U stock pile has been characterized by alpha spectroscopy and mass spectroscopic methods. In addition, this material has been radiochemically separated, to yield a supply of thorium that has been similarly characterized. The thorium fraction has shown a specific activity of approximately 37 kBq ²²⁹Th/ mg ²³²Th. Based upon the unique composition of the generator material, a manual process for milking the generator was developed before transitioning the operation to a semi-automated platform. Regular milking of the generator has yielded GBq quantities of purified ²²⁵Ac that has been provided to multiple collaborative research partners. Radionuclidic purity is consistently greater than 98% ²²⁵Ac, with less than 0.02% ²²⁵Ra and 0.0001% ²²⁹Th.

Conclusions: To support internal and collaborative research programs in Targeted Alpha Therapy, CNL has recently constructed a Th/Ac generator to regularly provide access to this valuable isotope. The recent results pertaining to this area of the research will be presented.