Fe-Mediated Self-Assembled Nanodrug for Tumor Microenvironment Activated Synergistic Ferroptosis-Based-Chemodynamic/Chemo Therapy and Magnetic Resonance Imaging

Due to the low drug concentration, glutathione (GSH)-based oxidative stress regulating system in target tissues, and serious side effects, doxorubicin (DOX) usually shows a suboptimal efficacy in clinical practice. The synergistic combination of DOX-based chemotherapy with iron ion-based chemodynamic therapy (CDT), sensitization of cancer cells by GSH depletion, and responsive targeted delivery of DOX have been regarded as a potential efficient strategy to improve the efficacy. Herein, benefiting from the strong lipoic acid-Fe3+ coordination, we synthesized the DOX@Fe3+-LA (DOX@FL) nanodrug with a one-pot method based on the Fe3+-DOX chelation, disulfide open-ring polymerization and self-assembly behavior of lipoic acid. The nanodrug showed a spherical, uniform morphology and a high loading of DOX and Fe. Under the tumor microenvironment, the nanodrug could synchronously release DOX and Fe, and then induce •OH generation and intracellular GSH depletion efficiently, showing a multimodality synergistic therapeutic effect in vitro and in vivo. Additionally, the DOX@FL showed pH- and GSH-responsive MRI due to the paramagnetism of Fe3+, suggesting that DOX@FL NPs be a simple, efficient, and multifunctional nanoplatform for cancer targeting treatment and MRI.