A pH-sensitive drug delivery system based on hyaluronic acid co-deliver doxorubicin and aminoferrocene for the combined application of chemotherapy and chemodynamic therapy

Abstract Doxorubicin is a broad-spectrum antineoplastic drug used in tumor therapy, its clinical application is limited by side effects on normal tissues. In this article, a pH-responsive drug delivery system (NPs(DOX/AFc)) with co-delivers doxorubicin (DOX) and aminoferrocene (AFc) was prepared by a two-step synthesis method including the oxidation of hyaluronic acid and Schiff base reaction. NPs(DOX/AFc) can be used in combination therapy of chemodynamic therapy (CDT) and chemotherapy (CT), thus the dosage of the chemotherapeutic drug DOX was reduced. The drug release behavior of NPs(DOX/AFc) in vitro showed that acid-responsive drug releases under the endosomal/lysosomal environment were 56.5% of DOX and 61.8% of AFc. In vitro toxicity experiments showed that DOX and AFc had synergistic effects (CI = 0.878). The results of intracellular ROS measurement and the mitochondrial membrane potential analysis showed that in tumor cells NPs(DOX4/AFc) induced more production of reactive oxygen species and more loss of the mitochondrial membrane potential. In short, this co-delivery system based on polymer prodrugs provides a new idea for the combined application of CT and CDT.