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 center dot 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.