Electrospun nanofiber-enabled cascade fenton-like/nitric oxide strategy for enhanced intraperitoneal chemotherapy in advanced gastric cancer with peritoneal metastases

Abstract

Advanced gastric cancer (GC) with peritoneal metastases (PM) remains challenging due to limited efficacy of conventional therapies and severe complications from intraperitoneal chemotherapy (IPC). To address these limitations, we have developed a novel therapeutic electrospun nanofiber (PTX/GSNO@HKUST-1/PLEA). This composite anti-cancer material enables the continuous release of the paclitaxel (PTX) within the abdominal cavity. Concurrently, it responds to the overexpression of glutathione (GSH) in the acidic environment of tumor cells, converting Cu²⁺ into Cu⁺. The generated Cu⁺ subsequently produces cytotoxic hydroxyl radicals (OH) via the Fenton reaction. Ultimately, Cu⁺ stimulates the release of nitric oxide (NO) from S-nitrosoglutathione (GSNO). The chemodynamic therapy (CDT) mediated by the Fenton reaction significantly enhances the efficacy of IPC. Additionally, NO mitigates the hypoxic state of tumor tissues and decreases the hypoxia-inducible factor protein-1α (HIF-1α) expression, thereby improving the sensitivity and effectiveness of both IPC and CDT. This multimodal therapy synergistically combines potent anticancer efficacy with high biocompatibility and safety. In a mouse model of PM, PTX/GSNO@HKUST-1/PLEA membranes effectively suppressed tumor growth, significantly reduced ascites formation, relieved cancer cachexia, and extended survival. These results highlight the substantial potential of this novel nanofiber membrane for treating PM in advanced GC cases.