Capturing an elusive but critical element: Natural protein enables actinium chemistry

Actinium-based therapies could revolutionize cancer medicine but remain tantalizing due to the difficulties in studying and limited knowledge of Ac chemistry. Current efforts focus on small synthetic chelators, limiting radioisotope complexation and purification efficiencies. Here, we demonstrate a straightforward strategy to purify medically relevant radiometals, actinium(III) and yttrium(III), and probe their chemistry, using the recently discovered protein, lanmodulin. The stoichiometry, solution behavior, and formation constant of the ²²⁸Ac³⁺-lanmodulin complex and its ⁹⁰Y³⁺/^natY³⁺/^natLa³⁺ analogs were experimentally determined, representing the first actinium-protein and strongest actinide(III)-protein complex (sub-picomolar K_d) to be characterized. Lanmodulin’s unparalleled properties enable the facile purification recovery of radiometals, even in the presence of >10⁺¹⁰ equivalents of competing ions and at ultratrace levels: down to 2 femtograms ⁹⁰Y³⁺ and 40 attograms ²²⁸Ac³⁺. The lanmodulin-based approach charts a new course to study elusive isotopes and develop versatile chelating platforms for medical radiometals, both for high-value separations and potential in vivo applications.