Glutathione Depletion-based PH-responsive Injectable Hydrogels for Synergistic Treatment of Colon Tumor

In this paper, a pH-sensitive chitosan-grafted phenylboronic acid (CS-BA)/polyvinyl alcohol (PVA) hydrogel was constructed based on dynamic borate bonding for loading chemotherapeutic drug cisplatin (CDDP) and divalent Cu (CS-BA/PVA-Cu-CDDP). The hydrogel can respond and degrade specifically in the simulative acidic tumor microenvironment (TME), and the released Cu can deplete glutathione (GSH) in tumor cells and generate Cu. It is worth noting that, Cu can further catalyze the Fenton-like reaction to generate cancer cell-toxic hydroxyl radicals (OH•). More importantly, the depletion of GSH resulted in a reduction of the CDDP-GSH binding, allowing a fast CDDP release within the tumor cells, which significantly enhanced its anti-tumor efficacy. Meanwhile, the significantly reduced GSH can also protect the generated OH• from removal and enhance its therapeutic effect. In vitro antitumor experiments demonstrated that the CS-BA/PVA-Cu-CDDP hydrogel has excellent biosafety and synergistic chemotherapy/chemodynamic therapy (CDT) to inhibit tumor growth. Organoid experiments further demonstrated that CDDP and Cu encapsulated in the hydrogel enhanced their therapeutic efficacy. This study reveals the potential application of CDDP and Cu in the combined therapy of colon cancer.