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 in vivo 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.

中文翻译：

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缺氧激活的前药使同步化疗和 HIF-1α 下调用于肿瘤治疗

HIF-1α在实体瘤中因缺氧而过度表达与耐药性和治疗失败密切相关。在此，我们构建了一种名为 YC-Dox 的缺氧激活前药。这种前药可以在缺氧条件下被激活并进行自焚以释放多柔比星 (Dox) 和 YC-1 半琥珀酸酯 (YCH-1)，它们可以分别执行化疗并导致 HIF-1α 下调。这种前药能够在缺氧时特异性释放 Dox 和 YCH-1，从而对缺氧癌细胞产生显着的协同效力和显着的细胞毒性选择性（> 8 倍），而不是正常氧的健康细胞。在体内 实验表明，这种前药可以选择性地针对缺氧的癌细胞，避免对正常细胞的不希望的靶向，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影响。