A charge reversal nanomedicine based on dual pH-responsive crosslinked dextran-based polysaccharide for synergistic cancer chemo/chemodynamic therapy

The clinical use of chemotherapy alone has been restricted by its unsatisfactory curative effects and serious adverse effects. Chemotherapy combined with chemodynamic therapy (CDT) has recently emerged as an effective strategy for pancreatic cancer therapy. However, CDT needs to overcome insufficient intracellular iron ions, deficient endogenous hydrogen peroxide, and increased cellular antioxidant defense. Herein, we synthetized a novel organic iron-based polysaccharide nanocarrier (FDC) consisting of dextran, carboxymethyl chitosan and ferrocene. After encapsulating doxorubicin and palmitoyl ascorbate (VP), a charge reversal nanoparticle (VDF NPs) based on FDC was developed with high stability, allowing for enhanced tumor accumulation and prolonged retention in blood. VDF NPs are triggered to release drugs by the pH-responsive hydrolysis of Schiff-base group, and amplify intracellular hydrogen peroxide and iron levels to generate highly toxic reactive oxygen species (ROS) by Fenton reaction. In vitro and in vivo investigations showed that VDF NPs enhanced the synergistic antitumor efficacy through apoptosis mediated by both ROS and doxorubicin and the decrease of cellular antioxidant defense, and reduced doxorubicin-induced systemic toxicity via the nanoformulation and palmitoyl ascorbate. This work provided a promising strategy to develop organic iron-based polysaccharide nanocarrier with good biocompatibility and biodegradability for clinical applications.