Abstract
Uniform, mesoporous copper(II) oxide nanospindles (CuO NSs) were synthesized via a method based on templated hydrothermal oxidation of copper in the presence of monodisperse poly(glycerol dimethacrylate-co-methacrylic acid) nanoparticles (poly(GDMA-co-MAA) NPs). Subsequent decoration of CuO NSs with a CaO(2) nanoshell (CuO@CaO(2) NSs) yielded a nanozyme capable of Cu(I)/Cu(II) redox cycling. Activation of the Cu(I)/Cu(II) cycle by exogenously generated H(2)O(2) from the CaO(2) nanoshell significantly enhanced glutathione (GSH) depletion. CuO@CaO(2) NSs exhibited a 2-fold higher GSH depletion rate compared to pristine CuO NSs. The generation of oxygen due to the catalase (CAT)-like decomposition of H(2)O(2) by CuO@CaO(2) NSs resulted in a self-propelled diffusion behavior, characteristic of a H(2)O(2) fueled nanomotor. These nanostructures exhibited both peroxidase (POD)-like and CAT-like activities and were capable of self-production of H(2)O(2) in aqueous media via a chemical reaction between the CaO(2) nanoshell and water. Usage of the self-supplied H(2)O(2) by the POD-like activity of CuO@CaO(2) NSs amplified the generation of toxic hydroxyl ((•)OH) radicals, enhancing the chemodynamic effect within the tumor microenvironment (TME). The CAT-like activity provided a source of self-supplied O(2) via decomposition of H(2)O(2) to alleviate hypoxic conditions in the TME. Under near-infrared laser irradiation, CuO@CaO(2) NSs exhibited photothermal conversion properties, with a temperature elevation of 25 °C. The combined GSH depletion and H(2)O(2) generation led to a more effective production of (•)OH radicals in the cell culture medium. The chemodynamic function was further enhanced by an elevated temperature. To assess the therapeutic potential, CuO@CaO(2) NSs loaded with the photosensitizer, chlorine e6 (Ce6), were evaluated against T98G glioblastoma cells. The synergistic combination of photodynamic, photohermal, and chemodynamic modalities using CuO@CaO(2)@Ce6 NSs resulted in cell death higher than 90% under in vitro conditions.