在低毒环境下激活的floxuridine寡合物
Kunihiko Morihiro1, Takuro Ishinabe1, Masako Takatsu2
1Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
Journal of the American Chemical Society
|March 2, 2021
概括
新的抗癌药物, 素素寡合物前药物, 被瘤缺氧激活. 在正常情况下,这些前体药物具有降低的毒性,并有效抑制小鼠的瘤生长.
科学领域:
- 核酸治疗药物
- 癌症微观环境
- 药前策略
背景情况:
- 由于细胞内释放氨酸,氨酸寡合物是抗癌药物,具有增强的细胞毒性.
- 临床应用受到选择性差的阻碍,导致健康细胞的非向效应.
- 固体瘤的特点是缺氧的微环境,为选择性药物激活提供了潜在的目标.
研究的目的:
- 为改善癌细胞选择性而开发低氧激活的氨酸寡合物前药物.
- 研究基于氧气水平的药物疗效的条件控制.
- 在瘤模型中评估这些新型前药的体内疗效.
主要方法:
- 设计和合成两种含有低氧反应部分的floxuridine寡合原药.
- 在正常氧 (20% O2) 和低氧 (1% O2) 条件下的体内细胞毒性测定.
- 在小鼠体内研究以评估瘤生长抑制.
主要成果:
- 与原始化合物相比,floxuridine寡合物预制剂在诺莫克西亚下表现出明显较低的细胞毒性.
- 在低氧条件下保持抗癌作用,与原始floxuridine寡合物相似.
- 在活小鼠中有效抑制瘤生长.
结论:
- 对低氧反应的floxuridine寡合物预制剂提供了在瘤微环境中的条件激活策略.
- 这种方法提高了选择性,并降低了非低毒性组织的毒性.
- 代表了一种控制寡核酸抗癌药物的新方法.
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