Abstract
Prodrug-based self-assembled nanoparticles (PSNs) with tailored responses to tumor microenvironments show a significant promise for chemodynamic therapy (CDT) by generating highly toxic reactive oxygen species (ROS). However, the insufficient level of intracellular ROS and the limited drug accumulation remain major challenges for further clinical transformation. In this study, the PSNs for the delivery of artesunate (ARS) are demonstrated by designing the pH-responsive ARS-4-hydroxybenzoyl hydrazide (HBZ)-5-amino levulinic acid (ALA) nanoparticles (AHA NPs) with self-supplied ROS for excellent chemotherapy and CDT. The PSNs greatly improved the loading capacity of artesunate and the ROS generation from endoperoxide bridge using the electron withdrawing group attached directly to C10 site of artesunate. The ALA and ARS-HBZ could be released from AHA NPs under the cleavage of hydrazone bonds triggered by the acidic surroundings. Besides, the ALA increased the intracellular level of heme in mitochondria, further promoting the ROS generation and lipid peroxidation with ARS-HBZ for excellent anti-tumor effects. Our study improved the chemotherapy of ARS through the chemical modification, pointing out the potential applications in the clinical fields.
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