Preclinical Study of CDH3-Targeted ⁸⁹Zr/¹⁷⁷Lu Theranostics in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is characterized by poor prognosis, limited therapeutic options, and low survival rates, underscoring the urgent need for novel and effective treatment strategies. This study aimed to investigate the potential of CDH3 as a theranostic target for TNBC and to develop a CDH3-based targeted radionuclide theranostic approach. Flow cytometry was used to analyze CDH3 expression, and a CDH3-overexpressing HCC1806 xenograft mouse model was established. The performance of the dual-functional probe ⁸⁹Zr/¹⁷⁷Lu-11E10C11 was systematically evaluated through radioligand binding, internalization, PET/CT imaging, and biodistribution assays. The anti-CDH3 monoclonal antibody 11E10C11 was labeled with either ⁸⁹Zr or ¹⁷⁷Lu to separately assess diagnostic capability and targeted antitumor efficacy. Results demonstrated that CDH3 was highly and specifically expressed in TNBC (HCC1806), with [⁸⁹Zr]Zr-DFO-11E10C11 clearly delineating tumor lesions (72 h SUVmax, 2.11 ± 0.31) and [¹⁷⁷Lu]Lu-DOTA-11E10C11 significantly inhibiting tumor growth (TGI, 74.94%) without inducing hematologic toxicity or damage to normal organs, indicating favorable safety. In conclusion, CDH3 is a promising theranostic target for TNBC, and the ⁸⁹Zr/¹⁷⁷Lu-11E10C11 dual-functional probe successfully achieved an integrated "diagnosis-therapy" strategy, offering a novel approach with translational potential for precision management of TNBC.