Cascade Amplifiers of Intracellular Reactive Oxygen Species Based on Mitochondria-Targeted Core–Shell ZnO-TPP@D/H Nanorods for Breast Cancer Therapy

Tumor cells are vulnerable to reactive oxygen species (ROS). However, it is still a challenge to induce ROS efficiently in tumor cells. In this study, cascade amplifiers of intracellular ROS based on charge-reversible mitochondria-targeted ZnO-TPP@D/H nanorods (NRs) were first developed for breast cancer therapy. The core–shell ZnO-TPP@D/H NR with a particle size of 179.60 ± 5.67 nm was composed of a core of a ZnO NR, an inner shell of triphenyl phosphonium (TPP), and an outer shell of heparin. Doxorubicin (DOX) was loaded on ZnO-TPP@D/H NRs with high drug loading efficiency of 22.00 ± 0.18%. The zeta potential of ZnO-TPP@D/H NRs varied from 24.00 ± 0.83 to −34.06 ± 0.87 mV after heparin coating, protecting ZnO-TPP@D/H NRs from nonspecific adsorption in circulation. Mitochondrial targeting was achieved after the degradation of heparin. Cellular uptake assays showed that ZnO-TPP@D/H NRs could accumulate in mitochondria. ROS generation assays showed that ZnO-TPP@D/H NRs could triple the intracellular ROS in 4T1 cells (highly metastatic breast cancer cells) than free DOX. Western blot demonstrated that ZnO-TPP@D/H NRs dramatically induced cell apoptosis in 4T1 cells. In vivo experiments suggested the antitumor potential of ZnO-TPP@D/H NRs