Zhong Changle, Lu Minghan, Pan Guanhao, You Xintong, Peng Yan, Zeng Shulan, Zhang Guohai
Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China.
Molecules. 2025 Jul 23;30(15):3081. doi: 10.3390/molecules30153081.
The tumor microenvironment plays an important role in tumor incidence, metastasis, and chemotherapy resistance. Novel therapeutic strategies targeting the tumor microenvironment have become a research focus in the field of biomedicine. In this study, we developed a smart small-molecule probe, , featuring pH/GSH dual-responsive characteristics. exhibits a unique pH-dependent reaction mechanism: GSH is preferentially covalently modified with maleimide groups in acidic microenvironments (pH < 7), while specifically activating nucleophilic substitutions under alkaline conditions (pH > 7). It is worth noting that effectively eliminates intracellular glutathione (GSH) in a time and concentration-dependent manner, demonstrating significant GSH depletion ability in various tumor cell lines. Pharmacodynamic studies have shown that not only inhibits the cell cycle by regulating the expression of cell cycle-related proteins, but also effectively suppresses the cloning ability of cancer cells. Furthermore, significantly increases the sensitivity of drug-resistant cancer cells to cisplatin. By integrating microenvironment modulation, real-time monitoring, and synergistic therapy, provides a novel molecular tool and theoretical basis for tumor theranostics integration.
肿瘤微环境在肿瘤的发生、转移及化疗耐药中发挥着重要作用。针对肿瘤微环境的新型治疗策略已成为生物医药领域的研究热点。在本研究中，我们开发了一种具有pH/谷胱甘肽（GSH）双响应特性的智能小分子探针， 。 具有独特的pH依赖性反应机制：在酸性微环境（pH < 7）中，GSH优先与马来酰亚胺基团发生共价修饰，而在碱性条件（pH > 7）下特异性激活亲核取代反应。值得注意的是， 能以时间和浓度依赖性方式有效消除细胞内谷胱甘肽（GSH），在多种肿瘤细胞系中表现出显著的GSH耗竭能力。药效学研究表明， 不仅通过调节细胞周期相关蛋白的表达来抑制细胞周期，还能有效抑制癌细胞的克隆能力。此外， 显著提高了耐药癌细胞对顺铂的敏感性。通过整合微环境调控、实时监测和协同治疗， 为肿瘤诊疗一体化提供了一种新型分子工具和理论基础。
