Design of a pH-Responsive Cu-Doped nanoplatform for Down-Regulating HIF-1α and enhancing Esophageal cancer chemotherapy

Introduction Esophageal cancer (EC) is the most malignant tumor posing great threat to human health. Chemotherapy, as the first-line treatment for EC, can not yield expected outcome due to chemo-resistance, low efficacy of monotherapy and off-target toxicity. Hence, it is imperative to develop one novel therapeutic strategy that can realize anti-drug resistance, tumor microenvironment response drug release, and integrated multi-modal therapy. Objectives Currently, treatment of EC faces great challenges. One pH-responsive nanoplatform, CDs-DOX-GOx@PEG (CDG@PEG), composed of copper-doped carbon dots (Cu-CDs), doxorubicin (DOX), glucose oxidase (GOx), and polyethylene glycol (PEG), was fabricated to realize better treatment of EC via multi-modal synergistic and targeted therapy. Methods Microscopy. The physicochemical properties of CDG@PEG were determined via TEM, XPS, XRD, FTIR and so on. The anti-tumor capacity was assessed with KYSE-30 cells and xenograft mice models. Moreover, the therapeutic mechanism was assessed by transcriptome, immunofluorescence and immunohistochemical analysis. Results Physiochemical characterization results showed that as designed nanoplatform was successfully fabricated and was endowed with outstanding pH-responsive and O 2 /ROS-generation capacities. In vitro , CDG@PEG exhibited excellent cell uptake and potent tumor cell-killing effect. In vivo, CDG@PEG displayed superior anti-tumor effect accompanied by good biocompatibility. Mechanistically, CDG@PEG realized the EC therapy by down-regulating drug-resistant genes (such as HIF-1α related genes), inducing mitochondria dysfunction, triggering cell apoptosis. Conclusion One multifunctional nanoplatform, CDG@PEG, was successfully prepared and it exhibited excellent in vitro and in vivo anti-tumor effect, which open new venues for developing novel therapeutic strategies for chemo-resistance cancer.