Abstract View

Introduction: In the field of nuclear medicine, significant attention has recently been directed to the development of alpha emitting radionuclides for targeted cancer therapy. Actinium-225 (Ac-225) is an alpha emitter with a convenient half-life of 9.92 days. This would make Ac-225 based radiopharmaceuticals deliverable over a wide geographic range and may allow for their relatively long shelf life (Tosato et al., Nucl.Med.Biol.,142-143: 108990, 2024).  There are a couple of methods for commercial manufacturing of Ac-225 as a raw material for drug manufacture, one of which involves cyclotron irradiation of a radium target using the Ra-226(p,2n)Ac-225 reaction (Nagatsu et al.,J.Nucl.Med.Mol.Imag., 49:279-289, 2021; Apostolidis et al.,Appl.Rad.Isotop.,62:383-387, 2005). For a product of pharmaceutical quality to be obtained, and in commercially relevant activity levels for support of ongoing clinical studies, a robust and reliable technology for Ac-225 separation from an irradiated solid Ra-226 target must be in place.

Method: Previous work (Nagatsu et al., J.Nucl.Med.Mol.Imag., 49:279-289, 2021) has described manual separation of Ac-225 from cyclotron irradiated solid Ra-226 target. In brief, the target is dissolved in nitric acid, and the produced Ac-225 is trapped, rinsed, and then eluted first from a DGA resin-filled cartridge and then from a LN resin-filled cartridge. The resulting crude Ac-225 product is left for sufficient time to allow for the undesirable Ac-226 isotope to decay to acceptable levels and the same purification step is repeated (Scheme 1). The final ion-exchange step results in an Ac-225 chloride in 0.1 M HCl solution. In our lab this method was implemented successfully and led to dry Ac-225 nitrate with the following preliminary specifications: ≥90%  radiolabeling efficiency with p-NO₂-Bn-DOTA chelating agent (radio-TLC); chemical purity showing ≤1.0 µg/MBq Ca ,Cu, Fe ,Zn, Pb, Al, Ba, Mn, Na (ICP-MS); radionuclidic purity ≥99% Ac-225 with ≤0.001% Ac-227 (gamma spectroscopy and ICP-MS). The goal of our study was to automate the process, making it suitable for further scale up in commercial manufacturing.

Results: Due to the long half-life of Ra-226 (1,600 years), for development purposes we chose to work with another radium isotope, Ra-223 (half-life 11.4 days). We successfully developed and tested a synthesis method on an automated radiochemistry module. The starting material for the process was a mixture of Ac-225 and Ra-223 in 0.7 M HNO₃. Using the same resins and similar reagent volumes as published previously, our fully automated process led to a solution of Ac-225 with radionuclidic purity suitable for further Ac-225 radiopharmaceutical developments and manufacturing. Current work applying our automated method to Ac-225 from Ra-226 separation is under way.

Conclusions: We have successfully automated the radiochemical separation of Ac-225 from Ra-223. It can potentially be applied for the separation and purification of Ac-225 nitrate from a cyclotron irradiated Ra-226 target. Current work is focused on further scale up and automation to result in Ac-225 supply in different chemical matrices.                                                                                                                                      

                                              Scheme 1  (Nagatsu et al., J.Nucl.Med.Mol.Imag., 49:279-289, 2021)