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 Cu²⁺ (CS-BA/PVA-Cu²⁺-CDDP). The hydrogel can respond and degrade specifically in the simulative acidic tumor microenvironment (TME), and the released Cu²⁺ 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-Cu²⁺-CDDP hydrogel has excellent biosafety and synergistic chemotherapy/chemodynamic therapy (CDT) to inhibit tumor growth. Organoid experiments further demonstrated that CDDP and Cu²⁺ encapsulated in the hydrogel enhanced their therapeutic efficacy. This study reveals the potential application of CDDP and Cu²⁺ in the combined therapy of colon cancer.