Floxuridine Oligomers Activated under Hypoxic Environment
Floxuridine Oligomers Activated under Hypoxic Environment
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DOI：
10.1021/jacs.0c10732
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发表时间：
2021-03-02
影响因子：
15
通讯作者：
Okamoto, Akimitsu
中科院分区：
文献类型：
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作者：
Morihiro, Kunihiko;Ishinabe, Takuro;Okamoto, Akimitsu
氟尿嘧啶低聚物是由多个氟尿嘧啶残基组成的抗癌寡核苷酸药物。它们对每个氟尿嘧啶单体表现出更强的细胞毒性，因为氟尿嘧啶低聚物的核酸酶降解直接在细胞中释放高活性的氟尿嘧啶单磷酸盐。然而，它们对癌细胞的低选择性限制了它们的临床应用。为了解决这一局限性，我们在此报告了在低氧条件下有效的氟尿嘧啶低聚前药，这是所有实体肿瘤微环境的显著特征之一。我们设计并合成了两种在碱基上具有低氧反应部分的氟尿嘧啶低聚前药。氟尿嘧啶低聚物前药在常氧条件下(O2=20%)表现出较低的细胞毒性，而母体氟尿嘧啶低聚物在低氧条件下(O2=1%)表现出相似的抗癌作用。氟尿嘧啶低聚物前药能够抑制活体小鼠的肿瘤生长。这将是第一个展示寡聚核苷抗癌药物药效有条件控制的例子。
Floxuridine oligomers are anticancer oligonucleotide drugs composed of a number of floxuridine residues. They show enhanced cytotoxicity per floxuridine monomer because the nuclease degradation of floxuridine oligomers directly releases highly active floxuridine monophosphate in cells. However, their clinical use is limited by the low selectivity against cancer cells. To address this limitation, we herein report floxuridine oligomer prodrugs that are active under hypoxia conditions, which is one of the distinguishing features of the microenvironment of all solid tumors. We designed and synthesized two types of floxuridine oligomer prodrugs that possess hypoxia-responsive moieties on nucleobases. The floxuridine oligomer prodrugs showed lower cytotoxicity under normoxia conditions (O-2 = 20%), while the parent floxuridine oligomer showed similar anticancer effects under hypoxia conditions (O-2 = 1%). The floxuridine oligomer prodrug enabled tumor growth suppression in live mice. This would be the first example demonstrating the conditional control of the medicinal efficacy of oligomerized nucleoside anticancer drugs.