Multifunctional Estrone–Polyoxometalate–F16 Hybrid Conjugate: A Synergistic Targeting Approach against Breast Cancer Cells

Polyoxometalates (POMs) are promising anticancer agents, but their use in clinical settings is hindered by their general toxicity and lack of tumor selectivity. In this study, we introduce a novel, dual-targeted hybrid compound (ESPOMF) based on an Anderson-type manganese polyoxomolybdate, designed to improve both potency and selectivity. This hybrid combines estrone, which targets estrogen receptors (ER), with F16, a mitochondria-targeting molecule, creating a multifunctional approach to breast cancer treatment. Cytotoxicity was assessed in ER-positive MCF-7, triple-negative MDA-MB-231 breast cancer cell lines, and normal HUVEC cells. ESPOMF showed the strongest anticancer effect, with IC₅₀ values of 88.45 ± 3.56 μg/mL (37.26 μM) in MCF-7 and 133.55 ± 4.25 μg/mL (56.27 μM) in MDA-MB-231, outperforming ESPOM, FPOM, and NaPOM. In HUVEC cells, toxicity was significantly lower (IC₅₀ = 281.40 ± 4.63 μg/mL or 118.56 μM), yielding selectivity indices of 3.18 (MCF-7) and 2.11 (MDA-MB-231). ICP-MS uptake analysis revealed that ESPOMF achieved 83.97% cellular uptake in MCF-7 cells after 24 h, approximately 20% higher than nontargeted FPOM (64.37%), supporting the role of estrone in ER-mediated endocytosis. Receptor saturation studies using 0.01 μM 17β-estradiol further confirmed ERα involvement in internalization. Apoptosis analysis by Annexin V/PI staining demonstrated that ESPOMF induced 71.5% total apoptosis at 24 h, increasing to 94.39% at 48 h, significantly exceeding the effect of other derivatives. Additionally, molecular docking showed high affinity of the POM core (ESPOM) for protein kinase CK2, with a binding energy of -9.19 kcal/mol and an estimated <i>K</i>_i of 0.184 μM, indicating CK2 inhibition as a key mechanistic pathway. In summary, ESPOMF integrates ER-targeting, mitochondrial disruption, and kinase inhibition into a single hybrid framework, resulting in enhanced efficacy and selectivity against breast cancer cells. This multifunctional strategy provides a compelling platform for future targeted cancer therapeutics.