Construction of Fe-doped ZIF-8/DOX nanocomposites for ferroptosis strategy in the treatment of breast cancer

Abstract

Breast cancer has become one of the top five commonest causes of cancer death. The use of ferroptosis to induce the generation of reactive oxygen species (ROS) in cancer cells presents a promising and potential strategy for cancer treatment. Herein, a series of facile bimetallic nanoparticles (x% Fe-doped ZIF-8) were synthesized and tested, and doxorubicin (DOX), a classic drug for breast cancer therapy, was encapsulated. After comparing the ratios of Fe²⁺/(Fe²⁺ + Zn²⁺), 7% Fe-doped ZIF-8 (7FZ) was found to be the most suitable particle for medical application. The drug loading efficiency of DOX@7FZ was 58.01 ± 0.02%. The pH-sensitive DOX@7FZ was degraded and DOX was released in lysosomes once internalized. Both the intracellular content of iron and ROS increased significantly. Meanwhile, the cell viability declined to 13.98% in 24 h at a concentration of 60 μg mL⁻¹ and the IC₅₀ was 42.68 μg mL⁻¹. Moreover, the expression of Bcl-2 and GPX-4 proteins decreased in a time-dependent manner, indicating that DOX@7FZ was able to enhance the ROS level in cancer cells via a synergistic effect between apoptosis and ferroptosis. The mechanism of action of DOX@7FZ was further verified using hematoxylin and eosin staining and immunohistochemical staining of Bcl-2 and GPX-4. These remarkable characteristics of DOX@7FZ may inspire further advancements in the treatment of breast cancer.