Breast cancer is one of the most threatening invasive cancer in women globally. Addressing this grand challenge, several promising chemotherapeutic reagents that target metastatic breast cancer have been successfully developed. However, the ability of cancer cells to become simultaneously resistant to different drugs, a trait named multidrug resistance (MDR), remains a major obstacle to successful clinical chemotherapy. 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 biodegradable multifunctional nanoparticle (Fe3O4@C@MnO2) based drug delivery system (DDS) for effectively killing metastatic breast cancer in vitro and in vivo. The 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. Specifically, excellent photothermal effect of the nanoparticle can cause high and long-term expression of heat shock factor-1 (HSF-1) trimers via a transit temperature change without damage normal organs nearby. The HSF-1 trimers repress the NF-κB pathway, which mediates 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. iRGD conjugated on our hybrid nanoparticle significantly enhances the tumor homing and penetration, thereby increasing cancer-killing efficiency and reducing side effects simultaneously. Furthermore, this theranostic nanoplatform also exhibits excellent biocompatibility and biodegradability. By targeting heterogenous MDR pathways in metastatic cancers and delivering anti-cancer drugs in a single platform, our multifunctional biodegradable hybrid nanoparticles represent a unique and promising solution for treating metastatic breast cancer.

A novel biodegradable multifunctional nanoplatform synergistically overcome multidrug resistance

256th National Meeting (2018)

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