Protein-Based Platform for Purification, Chelation, and Study of Medical Radiometals: Yttrium and Actinium

Abstract

Actinium-based therapies could revolutionize cancer medicine but remain tantalizing due to the difficulties in studying Ac chemistry. Current efforts focus on small synthetic chelators, limiting radioisotope complexation and purification efficiencies. Here we demonstrate how a recently discovered protein, lanmodulin, can be utilized to efficiently bind, recover, and purify medically-relevant radiometals, actinium(III) and yttrium(III), and probe their chemistry. The stoichiometry, solution behavior, and formation constant of the 228Ac-lanmodulin complex (Ac3LanM, Kd, 865 femtomolar) and its 90Y/natY/natLa analogues were experimentally determined, representing both the first actinium-protein and most stable actinide(III)-protein species 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 ultra-trace levels: down to 2 femtograms 90Y and 40 attograms 228Ac. 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 potentially in vivo applications.

Characterization of Americium and Curium Complexes with the Protein Lanmodulin: A Potential Macromolecular Mechanism for Actinide Mobility in the Environment

“…Log β 31 values of 31.9 and 32.5 were also determined for Pr 3 His LanM and Sm 3 His LanM. Given that Am 3+ has an ionic radius in the same range as Pr 3+ , Nd 3+ , and Sm 3+ (1.176, 1.161, and 1.131 Å, respectively), the results unequivocally demonstrate that LanM exhibits higher affinity for the actinides over the lanthanides of comparable ionic radius, a point supported by our recent comparison of Ac 3+ - versus La 3+ -bound LanM at radiotracer levels . The observation that the protein has slightly higher affinity for trivalent actinide ions over their lanthanide counterparts is reminiscent of prior characterization , of polyaminocarboxylate complexes.…”

“…The similarities between the coordination chemistry of lanthanides and trivalent actinides suggest that lanmodulin would also be an exceptional chelator for actinides. Indeed, we recently posted a preprint showing for the first time that LanM binds an actinide, the extremely rare but medically important actinium (Ac 3+ ), with 2-fold higher affinity than for La 3+ , the lanthanide closest in ionic radius, and also >2-fold higher affinity relative to Y 3+ . These results, in combination with the presence of LanM in numerous methylotrophs, prompted us to investigate LanM’s interactions with the heavy actinides, which are more environmentally relevant and hazardous than naturally occurring actinium isotopes (which only exist at tracer levels and have short half-lives) …”