The Key Laboratory for Chemical Biology of Fujian Province, The MOE Laboratory of Spectrochemical Analysis & Instrumentation, and Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China.
Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital, Xiamen University, Xiamen 361004, China.
Bioconjug Chem. 2021 May 19;32(5):983-990. doi: 10.1021/acs.bioconjchem.1c00131. Epub 2021 Apr 13.
The overexpression of HIF-1α in solid tumors due to hypoxia is closely related to drug resistance and consequent treatment failure. Herein, we constructed a hypoxia-activated prodrug named as YC-Dox. This prodrug could be activated under hypoxic conditions and undergo self-immolation to release doxorubicin (Dox) and YC-1 hemisuccinate (YCH-1), which could execute chemotherapy and result in HIF-1α downregulation, respectively. This prodrug is capable of specifically releasing Dox and YCH-1 in response to hypoxia, leading to a substantial synergistic potency and a remarkable cytotoxic selectivity (>8-fold) for hypoxic cancer cells over normoxic healthy cells. The experiments reveal that this prodrug can selectively aim at hypoxic cancer cells and avoid undesired targeting of normal cells, leading to elevated therapeutic efficacy for tumor treatment and minimized adverse effects on normal tissues.
由于缺氧导致的实体肿瘤中 HIF-1α 的过度表达与药物耐药性密切相关，并导致治疗失败。在此，我们构建了一种缺氧激活前药，命名为 YC-Dox。该前药可在缺氧条件下被激活，并进行自毁以释放阿霉素（Dox）和 YC-1 半琥珀酸酯（YCH-1），分别执行化疗并导致 HIF-1α 下调。该前药能够针对缺氧特异性释放 Dox 和 YCH-1，从而对缺氧癌细胞产生显著的协同效力和细胞毒性选择性（超过正常健康细胞的 8 倍）。实验表明，该前药可以选择性地针对缺氧癌细胞，避免对正常细胞的非预期靶向，从而提高肿瘤治疗的疗效，并最大限度地减少对正常组织的不良反应。
