点击化学选择性地激活一个auristatin原药与瘤内或全身瘤向剂
Jesse M McFarland1, Maša Alečković1, George Coricor1
1Shasqi Inc., 665 3rd St, Suite 501, San Francisco, California 94107, United States.
ACS central science
|July 31, 2023
概括
点击激活抗癌原药 (CAPAC) 平台使用点击化学精确地准瘤. 这种方法激活了强效的癌症药物,降低了毒性,并在临床前模型中显示出显著的抗瘤作用.
科学领域:
- 在瘤学瘤学.
- 化学生物学 化学生物学
- 药物运输 药物运输 药物运输
背景情况:
- 癌症药物的毒性限制了临床疗效.
- 在瘤部位的向药物激活是癌症治疗的关键目标.
- 点击化学为生物对等反应提供了一个精确的方法.
研究的目的:
- 评估针对药物激活的点击激活的抗癌原药 (CAPAC) 平台.
- 使用点击化学评估新型原药 (SQP22) 的疗效和毒性.
- 通过不同的向策略来证明瘤特异性药物激活.
主要方法:
- 开发一种原药 (SQP22) 通过修改单甲基奥里斯塔丁E与跨环氧 octene.
- 用于点击化学激活的使用了四素修饰的向剂 (SQL70和SQT01).
- 在小鼠瘤模型 (Karpas 299,RENCA) 和HER2阳性异种移植模型 (NCI-N87) 中测试了CAPAC平台.
主要成果:
- 与活性药物相比,SQP22在体外和体内的细胞毒性降低.
- 内注射SQL70与SQP22显示出显著的抗瘤活性.
- 在HER2阳性瘤中,SQT01与SQP22的系统性使用实现了针对性的抗瘤效果.
- 观察到的毒性是有限的,包括暂时的骨髓抑制和中度的体重减轻.
结论:
- 在CAPAC平台有效地激活癌症药物在瘤部位使用点击化学.
- 通过CAPAC实现向药物激活可以通过本地和系统的管理实现.
- 这种方法有望通过提高疗效和减少全身毒性来改善癌症治疗.
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