Reactive Oxygen Species-Activated Self-Accelerated Drug Release Nanoparticles for Enhanced Cancer Combination Therapy

Reactive oxygen species (ROS)-activated prodrugs offer high tumor selectivity due to an abnormal ROS level in tumor cells. However, effective prodrug activation is still limited by inadequate endogenous ROS. Here, we report a ROS-activated nanoparticle consisting of an iron-chelating polyprodrug. Due to its nanostructure, the nanoparticle can achieve effective tumor accumulation via the passive targeting effect. Activated by endogenous ROS in cancer cells, the thioacetal linkers in the nanoparticles will be broken to release cinnamaldehyde and chlorambucil. The former will increase the intracellular ROS level and accelerate drug release; the latter will induce the apoptosis of tumor cells. Therefore, the nanoparticle can realize self-accelerated drug release and a combination of chemotherapy and chemodynamic therapy. This work provides an endogenous ROS-activated self-accelerated drug release strategy to promote the selectivity and efficiency of drug delivery, enhancing cancer treatment.