Cu-64/Lu-177-Dota-Dizd, A Small-Molecule-Based Theranostic Pair For Triple-Negative Breast Cancer

Despite advances in targeted therapies, the prognosis for patients with triple-negative breast cancer (TNBC) is poor because there are few actionable molecular targets. The dependence of solid tumor growth on angiogenesis prompted our development of angiogenic-receptor-targeted radionuclide therapy (TRT) to treat TNBC by targeted delivery of therapeutic doses of ionizing radiation to tumors. A high-affinity vascular endothelial growth factor receptor (VEGFR)-targeted agent, diZD, was synthesized and labeled with Lu-177 and Cu-64 by 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator giving the TRT agent, Lu-177-DOTA-diZD, and PET imaging agent, Cu-64-DOTA-diZD. We showed that Cu-"64/Lu-177"-DOTA-diZD radiotracers are a promising theranostic pair for TNBC. 4T1-bearing mice treated with Lu-177-DOTA-diZD-based TRT survived with a median of 28 days, which was significantly longer than that of control mice as 18 days. Anti-PD1 immunotherapy resulted in a shorter median survival of 16 days. This work presents for the first time that small-molecule VEGFR-oriented TRT is a promising therapeutic option to treat "immunogenic cold" TNBC.