Hierarchical Fe3O4-DOX-TPP@HA Superparticles for Mitochondria-Targeted Photothermo-Chemotherapy of Breast Tumors

Abstract Nanodrug delivery systems have shown great potential for tumor therapy but still meet the challenge of precise and efficient targeting. In this work, we demonstrate a hierarchical approach for mitochondria-targeted photothermo-chemotherapy of a breast tumor by fabricating hyaluronic acid (HA)-coated Fe3O4 superparticles (SPs) that are co-loaded with doxorubicin (DOX) and triphenylphosphine (TPP) (Fe3O4-DOX-TPP@HA SPs). As assemblies of Fe3O4 nanoparticles (NPs), the SPs exhibit superparamagnetism and primary tumor tissue targeting with the assistance of an external magnetic field. Meanwhile, the coated HA affords secondary targeting by binding with CD44 high-expressed breast tumor cells. The high level of hyaluronidase in the tumor cell further leads to the degradation of HA and exposure of TPP, thus achieving TPP-mediated tertiary targeting toward mitochondria. In addition, the assembled Fe3O4 NPs endow the SPs with strong photothermal performance, which combines with the loaded DOX to achieve mitochondria-targeted photothermo-chemotherapy of breast tumor models efficiently in vivo. Furthermore, leveraging the superparamagnetism and strong near-infrared absorption of Fe3O4 SPs, multimodal monitoring in tumor therapy by magnetic resonance and photoacoustic imaging is allowed.