Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, PR China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang 310009, PR China; Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, Zhejiang 310009, PR China; National Innovation Center for Fundamental Research on Cancer Medicine, Hangzhou, Zhejiang 310009, PR China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, PR China.
MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, Zhejiang 310027, PR China.
J Colloid Interface Sci. 2025 Jan 15;678(Pt B):866-877. doi: 10.1016/j.jcis.2024.08.240. Epub 2024 Sep 6.
Disulfiram (DSF) is a safe drug with negligible toxicity and Cu-dependent anti-tumor efficacy. However, the accumulation and combination of DSF and Cu in non-tumor tissues leads to systemic toxicity owing to the formation of highly poisonous diethyldithiocarbamate (CuET). In addition, CuET-mediated tumor-killing reactive oxygen species may be weakened by intra-tumoral glutathione (GSH). Herein, a synergistic treatment was developed that utilized the oral delivery of DSF and an injectable polyphenol-copper (PA-Cu) hydrogel loaded with the glutamine uptake inhibitor 2-amino-4-bis(phenoxymethyl)aminobutane (V9302). The injectable hydrogels were synthesized by the Schiff base reaction of hydroxypropyl chitosan (HPCS) with a PA-Cu reversible cross-linking agent. Because of the dynamic coordination between PA and Cu, the PA-Cu/HPCS hydrogel gradually releases Cu, forming CuET with DSF. The released V9302 inhibits glutamine uptake, thereby suppressing GSH synthesis and enhancing the therapeutic efficacy of the in situ formed CuET. The synergistic effect of PA-Cu/HPCS/V9302 and DSF in eliminating intracellular GSH and killing tumor cells was validated by in vitro cell experiments. Animal experiments further confirmed that PA-Cu/HPCS/V9302 and DSF have an inhibitory effect on tumor growth while maintaining the biosafety of main organs.
双硫仑（DSF）是一种安全的药物，毒性可忽略不计，且具有铜依赖性的抗肿瘤功效。然而，DSF 和 Cu 在非肿瘤组织中的积累和结合导致形成高度有毒的二乙基二硫代氨基甲酸盐（CuET），从而引起全身毒性。此外，CuET 介导的杀伤肿瘤的活性氧可能会因肿瘤内谷胱甘肽（GSH）而减弱。在此，开发了一种协同治疗方法，利用 DSF 的口服给药和载有谷氨酰胺摄取抑制剂 2-氨基-4-双（苯氧甲基）氨基丁烷（V9302）的可注射多酚-铜（PA-Cu）水凝胶。可注射水凝胶是通过羟丙基壳聚糖（HPCS）与 PA-Cu 可逆交联剂的席夫碱反应合成的。由于 PA 和 Cu 之间的动态配位，PA-Cu/HPCS 水凝胶逐渐释放 Cu，与 DSF 形成 CuET。释放的 V9302 抑制谷氨酰胺摄取，从而抑制 GSH 的合成，并增强原位形成的 CuET 的治疗效果。通过体外细胞实验验证了 PA-Cu/HPCS/V9302 和 DSF 在消除细胞内 GSH 和杀伤肿瘤细胞方面的协同作用。动物实验进一步证实，PA-Cu/HPCS/V9302 和 DSF 对肿瘤生长具有抑制作用，同时保持主要器官的生物安全性。
