Cosby Alexia G, Arino Trevor, Bailey Tyler A, Buerger Matthew, Woods Joshua J, Aguirre Quintana Luis M, Alvarenga Vasquez Jennifer V, Wacker Jennifer N, Gaiser Alyssa N, Strong Roland K, Abergel Rebecca J
Chemical Sciences Division, Lawrence Berkeley National Laboratory Berkeley CA 94720 USA
Department of Nuclear Engineering, University of California Berkeley CA 94720 USA.
RSC Chem Biol. 2023 Jun 15;4(8):587-591. doi: 10.1039/d3cb00050h. eCollection 2023 Aug 3.
The mammalian protein siderocalin binds bacterial siderophores and their iron complexes through cation-π and electrostatic interactions, but also displays high affinity for hydroxypyridinone complexes of trivalent lanthanides and actinides. In order to circumvent synthetic challenges, the use of siderocalin-antibody fusion proteins is explored herein as an alternative targeting approach for precision delivery of trivalent radiometals. We demonstrate the viability of this approach , using the theranostic pair Y (β, = 64 h)/Y (β, = 14.7 h) in a SKOV-3 xenograft mouse model. Ligand radiolabeling with octadentate hydroxypyridinonate 3,4,3-LI(1,2-HOPO) and subsequent protein binding were achieved at room temperature. The results reported here suggest that the rapid non-covalent binding interaction between siderocalin fusion proteins and the negatively charged Y(iii)-3,4,3-LI(1,2-HOPO) complexes could enable purification-free, cold-kit labeling strategies for the application of therapeutically relevant radiometals in the clinic.
哺乳动物蛋白质铁调素通过阳离子-π和静电相互作用结合细菌铁载体及其铁络合物，但对三价镧系元素和锕系元素的羟基吡啶酮络合物也表现出高亲和力。为了规避合成挑战，本文探索使用铁调素-抗体融合蛋白作为一种替代靶向方法，用于三价放射性金属的精准递送。我们在SKOV-3异种移植小鼠模型中，使用治疗诊断用核素对Y（β，半衰期 = 64小时）/Y（β，半衰期 = 14.7小时）证明了该方法的可行性。在室温下用八齿羟基吡啶酮3,4,3-LI(1,2-HOPO)进行配体放射性标记并随后与蛋白质结合。本文报道的结果表明，铁调素融合蛋白与带负电荷的Y(iii)-3,4,3-LI(1,2-HOPO)络合物之间快速的非共价结合相互作用，可为临床上治疗相关放射性金属的应用实现免纯化、冷试剂盒标记策略。
