Zhang Xinyuan, Li Yu, Zhang Yanhui, Wang Shige, Zhao Jiulong, Wang Tianjiao
School of Health Science and Engineering, University of Shanghai for Science and Technology, No. 516 Jungong Road, Shanghai 200093, PR China; Department of Gastroenterology, Changhai Hospital, Naval Medical University, No. 168 Changhai Road, Shanghai 200433, PR China.
The Third Affiliated Hospital of Naval Medical University, No. 225 Changhai Road, Shanghai 200433, PR China.
Int J Biol Macromol. 2025 Mar;297:139557. doi: 10.1016/j.ijbiomac.2025.139557. Epub 2025 Jan 6.
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.
本文基于动态硼酸键构建了一种pH敏感的壳聚糖接枝苯硼酸（CS-BA）/聚乙烯醇（PVA）水凝胶，用于负载化疗药物顺铂（CDDP）和二价铜（CS-BA/PVA-Cu-CDDP）。该水凝胶能在模拟酸性肿瘤微环境（TME）中特异性响应并降解，释放出的铜可消耗肿瘤细胞中的谷胱甘肽（GSH）并生成Cu⁺。值得注意的是，Cu⁺可进一步催化类芬顿反应生成对癌细胞有毒性的羟基自由基（OH•）。更重要的是，GSH的消耗导致CDDP与GSH的结合减少，使CDDP在肿瘤细胞内快速释放，显著增强了其抗肿瘤疗效。同时，显著降低的GSH还可保护生成的OH•不被清除，增强其治疗效果。体外抗肿瘤实验表明，CS-BA/PVA-Cu-CDDP水凝胶具有优异的生物安全性和协同化疗/化学动力学疗法（CDT）以抑制肿瘤生长。类器官实验进一步证明，封装在水凝胶中的CDDP和铜增强了它们的治疗效果。本研究揭示了CDDP和铜在结肠癌联合治疗中的潜在应用。
