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Nuclide production and imaging applications of ²²⁵Ac for targeted alpha therapy

University of British Columbia

Targeted alpha therapies using actinium-225 (²²⁵Ac, t₁/₂ = 9.9 d) can treat advanced metastatic disease, yet insufficient ²²⁵Ac availability limits their development (63 GBq/year is produced globally via ²²⁹Th generators). This thesis describes efforts to produce ²²⁵Ac and apply multi-nuclide SPECT imaging in preclinical evaluation of ²²⁵Ac-radiopharmaceuticals. Initial ²²⁵Ac production used ᴺᵃᵗU-spallation-produced and mass-separated ion beams, producing up to 8.6 MBq of ²²⁵Ra (an ²²⁵Ac parent) and 18 MBq of ²²⁵Ac. This material helped characterize the performance of ²²⁵Ac decay chain imaging on a microSPECT/PET/CT scanner in terms of contrast recovery, spatial resolution, and noise. Larger ²²⁵Ac quantities were produced via thorium target irradiation with a 438 MeV, 72 μA proton beam for 36 hours, producing (521 ± 18) MBq of ²²⁵Ac and (91 ± 14) MBq of ²²⁵Ra. These irradiations enabled ²³²Th(p,x) cross sections measurements for ²²⁵Ac, ²²⁵Ra, and ²²⁷Ac: (13.3 ± 1.2) mb, (4.2 ± 0.4) mb, and (17.7 ± 1.7) mb, respectively. Thirty-five other cross sections were measured and compared to FLUKA simulations; measured and calculated values generally agree within a factor of two. Ac separation from irradiated thorium and co-produced radioactive by-products used a thorium peroxide precipitation followed by cation exchange and extraction chromatography. Studies showed this method separates Ac from most elements, providing a directly-produced Ac product (²²⁷˒²²⁵Ac†) with measured ²²⁷Ac content of (0.15 ± 0.04)%, a hazardous long-lived (t₁/₂ = 21.8 y) impurity with prohibitively low waste disposal limits. A second, indirectly-produced ²²⁵Ra/²²⁵Ac-generator-derived Ac product (²²⁵Ac*) with ²²⁷Ac content of <7.5x10⁻⁵% was also obtained. The thorium target design, the simulations benchmarked against newly measured cross sections, and the precipitation-based thorium target processing method are separate novel contributions that together form the first demonstration of ²²⁵Ac* production technology that can be scaled to useful clinical quantities. This thesis therefore presents the scientific foundation for a new potential ²²⁵Ac production paradigm that could substantially increase production of ²²⁷Ac-free ²²⁵Ac using accelerator-based methods that are independent of the fixed ²²⁹Th quantities available from ²³³U stockpiles. Such increased ²²⁵Ac supplies will be required for the widespread clinical adoption of emerging ²²⁵Ac-based targeted alpha therapies to be realized.

Text

2020-12-24

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/76900

Physics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/