Cobalt–nickel metal–organic frameworks (CNMs) as drug delivery agents for triple-negative breast cancer

Breast cancer is one of the most prevalent cancers worldwide, with triple-negative breast cancer (TNBC) representing a particularly aggressive subtype, making it difficult to treat, and is associated with a poor prognosis. However, chemotherapy is associated with challenges such as drug resistance, off-target toxicity, and limited efficacy, highlighting the need for more effective therapies. Nanocarriers, including liposomes, micelles, and dendrimers, offer improved drug delivery efficacy and reduced toxicity but face challenges in terms of stability and scalability. Metal-organic frameworks (MOFs) have emerged as promising drug delivery systems, particularly for combination therapies to overcome resistance in TNBC. In this study, cobalt-nickel metal-organic frameworks (CNMs) were synthesized and loaded with a combination of cisplatin (Cis), doxorubicin (Dox), and 5-fluorouracil (5-Fu) (MD-CNM) to develop a novel multidrug delivery system. The MD-CNM exhibited high biocompatibility, an efficient drug loading capacity of 95.44 ± 4.05%, and sustained release over 96 h. Moreover, the MD-CNM demonstrated potent cytotoxicity against MDA-MB-231 breast cancer cells, with an IC₅₀ concentration of 461 nM, which is two- to five-fold less than the IC₅₀ value of individual drugs (Cis, Dox, and 5-Fu) loaded with the CNM, indicating enhanced therapeutic efficacy. Additionally, flow cytometry analysis revealed that the MD-CNM induced necrosis (77.59%) and late apoptosis (12.37%) with cell cycle arrest in the G₀/G₁ phase, further confirming its anticancer potential. Furthermore, the <i>ex ovo</i> chorioallantoic membrane (CAM) assay demonstrated that the MD-CNM significantly inhibited tumor angiogenesis by downregulating key pro-angiogenic factors, including vascular endothelial growth factor A (VEGFA), fibroblast growth factor 2 (FGF2), and angiopoietin 1 (ANG1) within the tumor microenvironment. These findings underscore the potential of CNMs as an innovative and efficient multidrug delivery platform for targeted cancer therapy, particularly for treating TNBC, offering a promising alternative to conventional chemotherapy with improved efficacy and reduced toxicity.