Redox-Sensitive Ultrashort Peptide Hydrogel with Tunable Mechanical Properties for Anti-Tumor Drug Delivery

In this study, we report a new ultrashort peptide (LOC), which forms a redox-sensitive hydrogel after cross-linking with the mild oxidant H₂ O₂ and used it for tumor-targeted delivery of doxorubicin hydrochloride (DOX). LOC gelled within a few minutes in low-concentration H₂ O₂ solution. The concentration of H₂ O₂ significantly altered the gelation time and mechanical properties of the hydrogel. The in vitro micromorphology, secondary structure and rheology characterization of cross-linked hydrogels confirmed the sensitivity and injectability to reducing agent. The cross-linked hydrogel had a strong drug loading capacity, and the drug was released in a GSH concentration-dependent manner, following the Fick diffusion model. In addition, the cross-linked hydrogel showed no cytotoxicity to normal fibroblasts, and no damage to the subcutaneous tissue of mice was observed. In vitro cytotoxicity experiments showed that the DOX-hydrogel system exhibited good anti-cancer efficacy. In vivo studies using 4T1 tumor-bearing mice showed that the DOX-hydrogel system had a significant inhibitory effect on tumors. Therefore, the newly designed redox-sensitive hydrogel can effectively enhance the therapeutic efficacy of DOX and reduce toxicity, making it an attractive biological material.