Abstract
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 177Lu and 64Cu by 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator giving the TRT agent, 177Lu-DOTA-diZD, and PET imaging agent, 64Cu-DOTA-diZD. We showed that "64Cu/177Lu"-DOTA-diZD radiotracers are a promising theranostic pair for TNBC. 4T1-bearing mice treated with 177Lu-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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / therapeutic use*
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Cell Line, Tumor
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Coordination Complexes / chemical synthesis
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Coordination Complexes / therapeutic use*
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Copper Radioisotopes / chemistry
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Female
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Heterocyclic Compounds, 1-Ring / chemical synthesis
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Heterocyclic Compounds, 1-Ring / therapeutic use
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Lutetium / chemistry
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Mice
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Mice, Inbred BALB C
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Positron-Emission Tomography
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Precision Medicine / methods
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Radioisotopes / chemistry
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Radiopharmaceuticals / chemical synthesis
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Radiopharmaceuticals / therapeutic use*
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Receptors, Vascular Endothelial Growth Factor / metabolism
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Triple Negative Breast Neoplasms / diagnostic imaging
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Triple Negative Breast Neoplasms / drug therapy*
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Triple Negative Breast Neoplasms / metabolism
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Tumor Protein, Translationally-Controlled 1
Substances
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Antineoplastic Agents
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Coordination Complexes
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Copper Radioisotopes
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Copper-64
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Heterocyclic Compounds, 1-Ring
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Radioisotopes
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Radiopharmaceuticals
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Tpt1 protein, mouse
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Tumor Protein, Translationally-Controlled 1
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1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
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Lutetium
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Lutetium-177
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Receptors, Vascular Endothelial Growth Factor