TY - JOUR
T1 - 64Cu/177Lu-DOTA-diZD, a Small-Molecule-Based Theranostic Pair for Triple-Negative Breast Cancer
AU - Huang, Yuqian
AU - Yang, Zhen
AU - Li, Feng
AU - Zhao, Hong
AU - Li, Chun
AU - Yu, Nam
AU - Hamilton, Dale J
AU - Li, Zheng
N1 - Funding Information:
This work was supported by the Houston Methodist Research Institute (HMRI) and foundation. The authors thank the preclinical imaging core facility of HMRI. This research was funded in part through DoD BCRP Breakthrough Award (BC141561P1) (Z.L.) and Finger Distinguished Endowed Chair (D.H.).
Publisher Copyright:
©
PY - 2021/3/11
Y1 - 2021/3/11
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.0c01957
DO - 10.1021/acs.jmedchem.0c01957
M3 - Article
C2 - 33646782
SN - 0022-2623
VL - 64
SP - 2705
EP - 2713
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 5
ER -