5-Fluorouracil-containing inorganic iron oxide/platinum nanozymes with dual drug delivery and enzyme-like activity for the treatment of breast cancer
Zheng Nie, Yasaman Vahdani, William C. Cho, Samir Haj Bloukh, Zehra Edis, Setareh Haghighat, Mojtaba Falahati, Rasoul Kheradmandi, Laila A. Jaragh-Alhadad, Majid Sharifi
Abstract
Intrinsic enzyme-mimic activity of inorganic nanoparticles has been widely used for nanozymatic anticancer and antibacterial treatment. However, the relatively low peroxidase-mimic activity (PMA) and catalse-mimic activity (CMA) of nanozymes in tumor microenvironment has hampered their potential application in the cancer therapy. Therefore, in this study, we aimed to fabricate platinum (Pt) nanozymes dispersed on the surface of iron oxide (Fe3O4) nanosphere that, in addition to boosting the PMA and CMA, resulted in the formation of a pH-sensitive nano-platform for drug delivery in breast cancer therapy. After development of Fe3O4 nanospheres containing Pt nanozymes and loading 5-fluorouracil (abbreviated as: Fe3O4/[email protected] nanospheres), the physicochemical properties of the nanospheres were examined by electron microscopy, dynamic light scattering, zeta potential, X-ray diffraction, thermogravimetric, BET surface, and PMA/CMA analyses. Then, the cytotoxicity of the Fe3O4/[email protected] nanospheres against 4T1 cells was investigated by the cell counting kit-8 assay and flow cytometry. Also, the anticancer effect of fabricated nanoplatform was assessed in mouse bearing 4T1 cancer tumors, in vivo. The results showed that the Fe3O4/[email protected] nanospheres provide a platform for optimal FLU loading, continuous pH-sensitive drug release, and potential PMA and CMA to increase the level of ROS and O2, respectively. Cytotoxicity outputs showed that the Fe3O4/[email protected] nanospheres mitigate the proliferation of 4T1 cancer cells mediated by apoptosis and intracellular generation of reactive oxygen species (ROS). Furthermore, in vivo assays indicated a significant reduction in tumor size and overcoming tumor hypoxia. Overall, we believe that the developed nanospheres with dual enzyme-mimic activity and pH-sensitive drug delivery can be used for ROS/chemotherapy double-modality antitumor therapy.