Abstract：
Although chlorambucil (CHL) is a long-established anticancer drug, the drug failure of CHL, mediated by the intracellular defense system consisting of glutathione (GSH) and GSH S-transferase pi (GST-pi), has significantly limited the application of CHL. To overcome this issue, we first designed a GSH-responsive small-molecule prodrug (EA-SS-CHL) by combining CHL and ethacrynic acid (EA). Subsequently, drug-loaded nanoparticles (ECPP) were formed by the self-assembly between EA-SS-CHL and amphiphilic PEG-PDLLA to improve the water solubility of the prodrug and its ability to target tumor sites. Upon exposure to high intracellular GSH concentration, EA-SS-CHL gradually degrades, leading to the release of EA and CHL. The presence of EA facilitates the depletion of GSH and inhibition of GST-pi, ultimately attenuating the detoxification of the intracellular defense system to CHL. Cytotoxicity studies and apoptosis assays demonstrate that ECPP exhibits higher therapeutic efficiency than CHL. Additionally,in vivotumor suppression effects and biocompatibility provide further evidence for the superiority of ECPP. This work presents a promising strategy to enhance the efficacy of CHL in cancer therapy.
摘要：
虽然苯丁酸氮芥（CHL）是一种历史悠久的抗癌药物，CHL的药物失效，由谷胱甘肽（GSH）和谷胱甘肽S-转移酶pi（GST-pi）组成的细胞内防御系统介导，显著限制了CHL的应用。为了克服这个问题，我们首先设计了一种GSH反应性小分子前药(EA-SS-CHL),将CHL和依替炔酸(EA)结合使用。随后，通过EA-SS-CHL和两亲性PEG-PDLLA之间的自组装形成载药纳米颗粒(ECPP),以提高前药的水溶性和靶向肿瘤部位的能力。在暴露于高细胞内GSH浓度时，EA-SS-CHL逐渐降解，导致EA和CHL的释放。EA的存在促进GSH的消耗和GST-pi的抑制，最终削弱细胞内防御系统对CHL的解毒作用。细胞毒性研究和细胞凋亡测定表明ECPP比CHL表现出更高的治疗效率。此外,体内抑瘤作用和生物相容性为ECPP的优越性提供了进一步的证据。这项工作提出了一种有希望的策略，以增强CHL在癌症治疗中的功效。
