Cancer metastasis is one of the leading cause of death of breast cancer patients but currently there is lacking effective cure. Addressing this grand challenge, several promising chemotherapeutic reagents that target metastatic cancers have been successfully developed. Still, their long term clinical outcome has not been satisfactory and is significantly hurdled by major obstacles such as multidrug resistance (MDR), which is developed during repeated drug treatment. Additionally, due to the complex nature of tumor migration, and the strong side effects of anti-tumor drugs, MDR can be further compounded by the heterogeneous tumor microenvironment, which make it extremely challenging to prevent recurrence of metastasis.
To this end, we developed a hybrid multifunctional nanoparticle (Fe3O4@C@MnO2) based drug delivery system (DDS) for effectively killing metastatic cancer in vitro and in vivo. Unlike conventional nanoparticle based anticancer strategies, our hybrid nanoparticle based DDS not only target-specifically delivers anti-cancer reagents, but also downregulates important drug resistant pathways to achieve sensitization of cancer cells. More specifically, the multimodal photothermal effect of nanoparticle induces high and long-term expression of heat shock factor-1 (HSF-1) trimers in a breast cancer metastaic model, downregulates NF-κB and further suppresses anticancer drug effluxing machinery through MDR-1/P-gp expression. Meanwhile, MnO2 shell reacts with intracellular GSH in cancer cells, enabling target-specific drug release, generating Mn2+ for deep tissue tumor imaging, and directly sensitized metastasis cancer by modulating redox inside cancer cells in situ. Furthermore, iRGD conjugated on our hybrid nanoparticle significantly enhances the tumor homing and penetration, thereby increasing cancer-killing efficiency and reducing side effects simultaneously. By targeting heterogenous MDR pathways in metastatic cancers and delivering anti-cancer drugs in a single platform, our multifunctional hybrid nanoparticles represent a unique and promising solution for treating metastatic cancer in vivo.