Targeted alpha therapy (TAT) strategically delivers alpha-emitting radioisotopes to cancerous cells through biological targeting vectors. In particular, actinium-225 (²²⁵Ac; t_1/2= 9.92 days) TAT has garnered significant interest with promising clinical studies. Despite these advances, the fundamental coordination chemistry of Ac remains underdeveloped due, in part, to the limited supply of ²²⁵Ac and the poorly understood chelation behavior that is further magnified by the spectroscopic silence of the Ac^III electronic ground state (5f⁰6d⁰). To address these challenges, the longest-lived isotope of actinium (²²⁷Ac; t_1/2= 21.77 years) was used to serve as an analogue to the radiopharmaceutically relevant ²²⁵Ac isotope, as the half-life of ²²⁷Ac is more amenable to chemical studies that span hours to several days. Furthermore, our group has employed a protein (“siderocalin”) to serve as a macromolecular host for ²²⁷Ac. Siderocalin binds siderophores and their ferric complexes as part of the mammalian innate immune system, but has also been shown to selectively bind a diverse range of actinide-siderophore complexes. Collectively, we leveraged structural and spectroscopic signatures of both a siderophore chelator and protein host to probe solution thermodynamics and coordination behavior of an Ac^III complex. Ac^III-chelator-macromolecule complexes will be discussed not only in the context of actinide bonding and periodicity, but also aimed towards broader scopes in radiotherapeutics.

Marc Allaire

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