Reactive oxygen species-responsive Pluronic F127 hyaluronic hydrogel for targeted doxorubicin delivery in glioblastoma and enhanced survival with radiotherapy.

Hydrogel systems have been developed for the localized delivery of drugs targeting tumors; however, they undergo rapid degradation and lack precise manipulation of drug release, limiting their effectiveness. Therefore, we designed a material capable of localized drug delivery to the tumor microenvironment (TME). We synthesized a novel thermosensitive hydrogel (CF127) by modifying Pluronic F127 with l-cystine to promote disulfide bond formation, enabling a reactive oxygen species (ROS)-sensitive drug release mechanism triggered by the internal TME and external radiation. Incorporating hyaluronic acid (HA) improved the hydrogel mechanical strength, which increased the retention time, based on evidence of cohesion and dissolution resistance after radiation. Radiation triggered doxorubicin release from the CF127/HA hydrogel carrier. H2O2/dithiothreitol experiments, mimicking TME under radiation, demonstrated the ROS-responsiveness of the CF127/HA system. Furthermore, the CF127/HA system significantly increased drug retention, reduced toxicity to healthy brain tissues, and improved survival by 83%, which exceeded 2 months in glioblastoma multiforme-bearing mice. These findings indicate that the ROS-responsive thermosensitive hydrogel enabled efficient chemotherapeutic delivery for combined use with radiotherapy.