Combined Delivery of CuO Nanoparticles and HIF‐1α Inhibitor Acriflavine for Synergistic Local Treatment of Glioblastoma

Glioblastoma multiforme (GBM), the most common and highly aggressive primary malignant central nervous system tumor, has seen minimal improvement in its median survival of <24 months. This study investigates the codelivery of copper oxide nanoparticles (CuO NPs) and acriflavine (ACF), a hypoxia‐inducible factor‐inhibiting drug, to provide synergistic dual reactions in order to effectively kill tumor‐initiating cells and to target multiple processes implicated in GBM progression. The two anticancer agents are embedded in polymeric core‐sheath nanofibers formed by coaxial electrospinning. Transmission electron microscopy and dispersive X‐ray spectroscopy mapping are used to confirm the uniform distribution of CuO NPs in the fiber core. Fourier transform infrared spectroscopy and thermogravimetric analysis results suggest that drug‐core polymer interactions mainly occur through weak bonding with the solvent surrounding the core‐polymer chains, leading to a relatively faster drug release. Cytotoxicity of combinations of drugs is evaluated in vitro against the GL261‐LUC cell line, showing a very strong synergistic effect. Dose‐effect‐based model presents the average combination index of ≈0.48 and dose reduction index of 19.6 for ACF and 2.6 for CuO NPs. A 3D GBM spheroid model is utilized to better mimic the tumor microenvironment, including cell heterogeneity and hypoxic conditions.