Actinium-225 supply: thorium stocks, accelerators and radium targets

Actinium-225 (half-life 9.9 days) delivers four alpha particles per decay chain, which is why it is being tested attached to PSMA ligands, somatostatin analogues and other carriers in Phase 3 programmes by Novartis, Bristol Myers Squibb (through RayzeBio), Bayer, AstraZeneca and others. Historically the world's supply came from thorium-229 that itself decays from uranium-233 held by the US Department of Energy, milked from generators at Oak Ridge National Laboratory and by the Institute for Transuranium Elements in Karlsruhe, and amounted to enough for only a few thousand patient doses a year. That is the binding constraint on targeted alpha therapy.

Four routes are being built. First, more thorium-229: TerraPower Isotopes is extracting it from DOE uranium-233 as the material is downblended, and is building a production plant in Philadelphia. Second, high-energy proton spallation of thorium-232 at the DOE Tri-Lab effort (Brookhaven, Los Alamos and Oak Ridge), which yields large quantities contaminated with a small fraction of long-lived actinium-227 that complicates waste and regulatory acceptance. Third, radium-226 targets irradiated on medium-energy cyclotrons (the (p,2n) reaction), pursued by Eckert & Ziegler, Nusano, Ionetix and others, and photonuclear irradiation of radium with electron accelerators (NorthStar, Niowave), both of which depend on recovering and handling legacy radium sources. Fourth, in-house production by the sponsors themselves, as RayzeBio and Bayer have set up. The US DOE Isotope Program, the IAEA and industry groups track the totals; the pharmacopoeial question of how much actinium-227 is acceptable in a drug is unsettled and affects which routes can supply approved products. Lead-212, made from thorium-228 generators by Orano Med, is the main alpha-emitting alternative with its own supply chain.