School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
J Med Chem. 2021 Apr 22;64(8):4450-4461. doi: 10.1021/acs.jmedchem.0c00897. Epub 2021 Apr 5.
Overexpression of glucose transporters (GLUTs) in colorectal cancer cells is associated with 5-fluorouracil (, 5-FU) resistance and poor clinical outcomes. We designed and synthesized a novel GLUT-targeting drug conjugate, triggered by glutathione in the tumor microenvironment, that releases 5-FU and GLUTs inhibitor (phlorizin () and phloretin ()). Using an orthotopic colorectal cancer mice model, we showed that the conjugate exhibited better antitumor efficacy than 5-FU, with much lower exposure of 5-FU during treatment and without significant side effects. Our study establishes a GLUT-targeting theranostic incorporating a disulfide linker between the targeting module and cytotoxic payload as a potential antitumor therapy.
在结直肠癌细胞中葡萄糖转运蛋白（GLUTs）的过表达与 5-氟尿嘧啶（5-FU）耐药和不良临床结局相关。我们设计并合成了一种新型 GLUT 靶向药物偶联物，该偶联物在肿瘤微环境中受谷胱甘肽触发，释放 5-FU 和 GLUTs 抑制剂（根皮苷（phlorizin）和根皮素（phloretin））。我们使用结直肠原位癌小鼠模型表明，与 5-FU 相比，该偶联物表现出更好的抗肿瘤疗效，在治疗过程中 5-FU 的暴露量更低，且没有明显的副作用。我们的研究建立了一种 GLUT 靶向治疗策略，将靶向模块和细胞毒性有效载荷之间的二硫键连接起来，作为一种潜在的抗肿瘤治疗方法。
