Multifunctional Estrone–Polyoxometalate–F16 Hybrid Conjugate: A Synergistic Targeting Approach Against Breast Cancer Cells Publisher Pubmed



Ahmadi M ; Sadeghi F ; Soltanabadi A ; Sadeghialiabadi H ; Rostami M
Source: ACS Applied Bio Materials Published:2025

Abstract

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 IC50values 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 Kiof 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. © 2025 Elsevier B.V., All rights reserved.