CPOS Seminar: "Delivering radioactive metals for cancer treatment through metal-based cycloaddition"

Speaker: Grant J. Stec, Ph.D., Department of Chemistry and Biochemistry, UCSB

Targeted radionuclide therapy (TRT) is a highly effective method of cancer treatment which delivers radionuclides to malignant cells. The radioactive emissions from these radionuclides induce cellular damage that leads to cell death of the targeted malignancies. The targeted and selective delivery of this radioactive payload is achieved either by leveraging the intrinsic biodistribution of the radiopharmaceutical or by attaching specific targeting vectors (e.g., antibodies and peptides) to the radiolabeled complexes. Alternatively, specific cells and/or subcellular components can be pre-targeted with various vectors, then the radiolabeled complex can subsequently react with the targeting vector in a bioorthogonal manner. Here, we report L³MO₃ complexes, where L³ is a tridentate chelator (tris(pyrazolyl)hydrborate (Tp) or tris(3,5-dimethylpyrazolyl)methane (Tpm*)), and M is a radioactive transition metal (technetium-99m or rhenium-188), which undergo rapid “click” reactions with strained alkenes under mild conditions. Unlike conventional bioorthogonal cycloadditions which utilize covalent linkages between organic reactive partners, this system leverages a cycloaddition occurring at the inorganic MO₃ core. This method will enable a fundamental understanding of subcellular radiobiological effects as well as provide a potential strategy for treating radiation-resistant malignancies.