Esophageal cancer (EC) is a highly malignant tumor that poses a significant threat to patient survival. Chemotherapy, a mainstay treatment for EC, often yields unsatisfactory outcomes due to chemotherapy resistance, the low efficacy of monotherapy and off-target toxicity. Therefore, it is imperative to develop one novel therapeutic strategy capable of overcoming drug resistance, enabling tumor microenvironment-responsive drug release, and achieving multimodal synergistic therapy. Currently, treatment of chemotherapy-resistant EC (CREC) faces great challenges. To address this, a pH-responsive nanoplatform, CDs-DOX-GOX@PEG (CDG@PEG), composed of iron-doped carbon dots (Fe-CDs), doxorubicin (DOX), glucose oxidase (GOX), and polyethylene glycol (PEG), was fabricated to improve CREC treatment through synergistic and targeted therapy. The physicochemical properties of CDG@PEG were characterized using TEM, XPS, XRD, FTIR and other techniques. Its anti-tumor efficacy was assessed with DOX-resistant KYSE-30 cells and corresponding xenograft mouse models. Moreover, the underlying therapeutic mechanism was further investigated via transcriptomic, immunofluorescence and immunohistochemical analyses. Physicochemical characterization results showed that the designed nanoplatform was successfully fabricated, which was endowed with outstanding pH-responsive behavior and O₂/ROS-generation capabilities. In vitro, CDG@PEG demonstrated excellent cellular uptake and potent tumor cell-killing capacities. In vivo, it displayed superior anti-tumor efficacy with good biocompatibility. Mechanistically, CDG@PEG realized the CREC therapy by down-regulating drug-resistant genes (such as HIF-1α related genes), inducing mitochondrial dysfunction, and triggering cell apoptosis. This work opened new avenues for developing novel therapeutic strategies against chemotherapy-resistant cancers.
Wang et al. (Sun,) studied this question.