An injectable multimodal thiolated carboxymethyl cellulose hydrogel for advanced gastric cancer treatment

Chemotherapy is a standard preoperative treatment for locally advanced resectable gastric cancer (GC). However, its efficacy is often limited by the high intracellular glutathione (GSH) levels in tumor cells, which diminish the effectiveness of chemotherapeutic agents. In this study, we developed a GSH-sensitive injectable hydrogel, T-CMC@Fe 3+ (5-FU + GOx), incorporating ferric ions (Fe 3+ ), glucose oxidase (GOx), and 5-fluorouracil (5-FU) for advanced GC multimodal treatment. The hydrogel synergistically enhances anti-tumor activity through multiple mechanisms, including chemodynamic therapy, starvation therapy, and chemotherapy. Thiolated carboxymethyl cellulose (T-CMC) was synthesized by grafting L-cysteine onto carboxymethyl cellulose, with successful preparation confirmed by XPS, FTIR, and 13 C NMR characterizations. The T-CMC@Fe 3+ hydrogel demonstrated responsive degradation of GSH and exhibited favorable biocompatibility in co-culture experiments with GES-1 cells. In vitro analyses revealed that the T-CMC@Fe 3+ (5-FU + GOx) hydrogel significantly enhanced anti-tumor efficacy compared to chemotherapy alone, reducing cell viability to 12.28 ± 2.88 % after 48 h. In vivo studies using cell-derived and patient-derived xenograft models further confirmed its potent anti-tumor effects, with a marked reduction in tumor volume by 14 days (8.12 ± 4.89 mm 3 ). These findings highlight the potential of the T-CMC@Fe 3+ (5-FU + GOx) hydrogel as a novel and effective strategy for enhancing GC treatment through its multimodal therapeutic approach.