Biocompatible hydrogel co-delivering salvigenin and iridium (III) complex overcomes cancer stemness and cisplatin resistance in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) remains a challenging disease due to its aggressive nature and resistance to conventional treatments. This study presents an innovative injectable hydrogel (Ir-SAL@SA-CS) combining an iridium(III) complex with the natural flavonoid Salvigenin in a sodium alginate-chitosan matrix, designed to enhance therapeutic outcomes and reduce toxicity. In vitro experiments on TE6 and KYSE150 esophageal cancer cell lines demonstrated that this dual-drug hydrogel significantly reduced cell viability, with IC₅₀ values of approximately 31 µg/mL and 16 µg/mL, respectively, which is better than that of cisplatin. Normal esophageal cells (Het-1A) remained over 60 % viable at higher concentrations, indicating strong biocompatibility. Mechanistic studies revealed that the Ir-SAL@SA-CS induces mitochondrial dysfunction and elevates reactive oxygen species, triggering apoptosis in cancer cells. In vivo, intratumoral administration in a mouse xenograft model nearly eradicated tumor growth without affecting body weight or the function of vital organs. Serum markers and histopathology confirmed minimal systemic toxicity. RT-PCR results showed marked downregulation of stemness-related genes (Nanog, SOX2, OCT4), suggesting effective targeting of cancer stem cells. Compared to cisplatin, Ir-SAL@SA-CS demonstrated enhanced antitumor activity and a safer profile. These findings support the potential of combining metal complexes and natural agents within injectable hydrogels as a promising strategy for treating esophageal cancer.