A bifunctional drug delivery system with targeting and glutathione-responsivity amphiphiles for effective tumor therapy

A B S T R A C T Drug delivery systems utilizing tumor targeting, microenvironment responsiveness, and combination therapy have demonstrated advantages in antitumor research by enhancing efficacy and reducing side effects. In this study, a bifunctional amphiphilic carrier material (HA-SSS-MC) with targeting and glutathione-responsive properties was developed by linking hydrophilic hyaluronic acid (HA) and hydrophobic methyl cholate (MC) via a trisulfide bond. The photosensitizer zinc phthalocyanine (ZnPc) and the chemotherapeutic drug 5-fluorouracil (5-FU) were encapsulated within the amphiphiles to form dual drug-loaded nanomicelles (HA-SSS-MC/5-FU/ZnPc). These nanomicelles exhibited high drug loading efficiency, stability, and glutathione (GSH)-sensitive release properties. Notably, the singlet oxygen quantum yield of the drug-loaded nanomicelles was significantly higher than that of the free photosensitizer under high glutathione conditions. In vitro cellular assays confirmed that HA-SSS-MC/5-FU/ZnPc nanomicelles exhibited low cytotoxicity and demonstrated a significant cancer cell-killing effect, surpassing Free 5-FU or ZnPc alone. Furthermore, the nanomicelles showed targeting capabilities and accumulated within endosomes. In A549 tumor-bearing mice, HA-SSS-MC/5-FU/ZnPc exhibited the strongest antitumor efficacy and the lowest toxicity compared to all other groups. In conclusion, the targeted GSH-responsive dual drug-carrying nanomicelles will be a promising strategy for cancer therapy.