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Life sciences · Journal article
Molecular Pharmaceutics · September 23, 2026
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Abstract The absence of estrogen receptor, progesterone receptor, and HER2 expression limits the utility of targeted therapies in triple-negative breast cancer (TNBC). Chemotherapy is the standard of care for advanced TNBC but offers limited responses and an overall poor prognosis. We have developed several tumor-selective alkylphosphocholine analogs (NM600) for radiopharmaceutical therapy (RPT) of TNBC. Herein, we investigate the preclinical [225Ac]Ac-NM600 therapeutic efficacy and safety in two murine models of TNBC. NM600 was radiolabeled with 225Ac following previous methods. In vitro cytotoxicity studies were performed in metastatic (4T1) and non-metastatic (4T07) murine TNBC cells. Monte Carlo-based 225Ac dosimetry estimates enabled viability and clonogenic survival measurements in cells treated with 225Ac (0.03−1 Gy). Longitudinal ex vivo biodistribution studies were performed in BALB/c mice bearing 4T1 or 4T07 tumor grafts injected with 9.25 kBq [225Ac]Ac-NM600 at 24, 72, 120, and 144 h post-injection (p.i.), and dosimetry estimation was performed using a MIRD formalism and a standard mouse model. Therapeutically, three groups of mice bearing 4T1 or 4T07 grafts (n ⦥5) received IV injections of vehicle, or 9.25 or 18.5 kBq [225Ac]Ac-NM600. Tumor volume and overall survival were monitored thrice weekly. Toxicity was evaluated in separate groups of BALB/c mice (n = 3) at days 7, 30, 60, and 120 p.i. through complete blood count (CBC), serum chemistry, and histopathological analysis. [225Ac]Ac-NM600 was produced with high purity and serum stability. Clonogenic assays showed comparable dose-dependent 225Ac cytotoxicity in 4T1 and 4T07 cells, with an RBE of 5 compared to EBRT. Ex vivo biodistribution exhibited elevated and persistent tumor uptake, resulting in absorbed dose coefficients of 46 Gy/μCi and 42 Gy/μCi. Due to the hepatobiliary excretion of [225Ac]Ac-NM600, distribution in normal tissues was most prominent in the liver, with absorbed doses of 57 Gy/μCi and 63 Gy/μCi for mice bearing 4T1 and 4T07 tumors, respectively. Among other relevant tissues, blood and lungs were initially elevated but rapidly declined over time. [225Ac]Ac-NM600-treated mice exhibited significant tumor growth inhibition (p ≤ 0.015), with median survival of 21, 49, and 32 days, or 30, 77, and 64 days, for the vehicle, 9.25 kBq, and 18.5 kBq groups, in mice bearing 4T1 or 4T07 tumors, respectively. Only mild effects and no treatment-related mortality were observed in animals given [225Ac]Ac-NM600 9.25 or 18.5 kBq. Our findings underscore the potential of [225Ac]Ac-NM600 as a promising therapeutic agent for TNBC, warranting further assessments of efficacy and potential toxicities in additional TNBC animal models.