A Paclitaxel Prodrug with Copper Depletion for Combined Therapy toward Triple-Negative Breast Cancer

Tuning the content of copper is of great significancefor the treatmentof cancer and neurodegenerative diseases. Herein, we synthesized aredox-responsive paclitaxel (PTX) prodrug by conjugating PTX witha copper chelator through a disulfide bond. The as-fabricated prodrug(PSPA) showed specific chelation toward copper ions and could assemblewith distearoyl phosphoethanolamine-PEG(2000) to form stablenanoparticles (PSPA NPs) in aqueous media. Upon being internalizedby tumor cells, PSPA NPs could respond to high levels of redox-activespecies inside cells and efficiently release PTX. The copper chelatorcould increase oxidative stress- and abnormal metabolism-induced celldeath through intracellular copper depletion. The combination of chemotherapyand copper depletion therapy generated an enhanced therapeutic outcometoward triple-negative breast cancer with an ignorable systemic toxicity.Our work may provide insight into the combination of metabolic regulationand chemotherapy for combating malignant tumors.