A Tumor-Specific Ferric-Coordinated Epigallocatechin-3-gallate cascade nanoreactor for glioblastoma therapy

INTRODUCTION: Numerous options for treatment of glioblastoma have been explored; however, single-drug therapies and poor targeting have failed to provide effective drugs. Chemotherapy has significant antitumor effect, but the efficacy of single-drug therapies in the clinic is limited over a long period of time. Thus, novel therapeutic approaches are necessary to address these critical issues. OBJECTIVES: The present study, we investigated a tumor-specific metal-tea polyphenol-based cascade nanoreactor for chemodynamic therapy-enhanced chemotherapy. METHODS: HA-EGCG was synthesized for the first time by introducing epigallocatechin-3-gallate (EGCG) into the skeleton of hyaluronic acid (HA) with reducible disulfide bonds. A rapid and green method was developed to fabricate the metal-tea polyphenol networks (MTP) with an HA-EGCG coating (DOX@MTP/HA-EGCG) based on Fe(3+) and EGCG for targeted delivery of doxorubicin hydrochloride (DOX). GL261 cells were used to evaluate the antitumor efficacy of the DOX@MTP/HA-EGCG nanoreactor in vitro and in vivo. RESULTS: DOX@MTP/HA-EGCG nanoreactors were able to disassemble, resulting in escape of their components from lysosomes and precise release of DOX, Fe(3+), and EGCG in the tumor cells. HA-EGCG depleted glutathione to amplify oxidative stress and enhance chemodynamic therapy. The results of in vivo experiments suggested that DOX@MTP/HA-EGCG specifically accumulates at the CD44-overexpressing GL261 tumor sites and that sustained release of DOX and Fe(3+) induced a distinct therapeutic outcome. CONCLUSIONS: The findings suggested the developed nanoreactor has promising potential as a future GL261 glioblastoma therapy.