开发脂质体系统,以增强双价PROTACs的PK特性
Ponien Kou1, Elizabeth S Levy1, An D Nguyen1
1Small Molecules Pharmaceutics, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
Pharmaceutics
|August 26, 2023
概括
脂质体封装改善了双价蛋白质溶解向嵌合体 (PROTACs) 的药理动力学. 这种药物输送系统可以提高血度,从而有可能将PROTAC推向临床使用.
科学领域:
- 药物输送系统 药物输送系统
- 药理学 药理学是指药理学的学科.
- 生物技术是生物技术.
背景情况:
- 蛋白质溶解向金马 (PROTACs) 是一种新兴的药物开发技术,在临床试验中有几个候选者.
- 由于复杂的物理化学性质,特别是高脂性质,双对应的PROTAC在临床进展中面临挑战.
- 脂质体封装提供了一种策略,可以改善像PROTACs这样的脂性药物的药理动力学 (PK) 特性.
研究的目的:
- 开发和描述用于静脉注射双价PROTACs的脂质体系统.
- 增强两个双价PROTAC分子 (GNE-01和GNE-02) 的PK特性,特别是降低清除率和增加系统覆盖率.
- 评估不同脂质体配方 (PROTAC-in-cyclodextrin与常规脂质体) 在调节PROTAC血度方面的疗效.
主要方法:
- 开发和描述一个PROTAC-in-cyclodextrin脂质体系统,用于在脂质体核中封装双价PROTAC.
- 在小鼠和老鼠的药理动力学 (PK) 研究中,将脂质体配方与GNE-01和GNE-02的溶液配方相比较,剂量为1mg/kg.
- 在体内监测脂质和药物度,以评估药物释放动力学和与脂质清除 (CL) 的相关性.
主要成果:
- 与溶液相比,PROTAC-in-cyclodextrin脂质体配方对GNE-01显著增强了PK,AUC在小鼠和大鼠的AUC分别增加了80倍和380倍.
- 对于GNE-02,PROTAC-in-cyclodextrin脂酶体系统的结果是与小鼠的溶液配方相比,血度增加了23倍,与相关的脂质和药物清除相关.
- 对于GNE-02的常规脂质体配方,AUC增加了5倍,药物清除速度比脂质清除更快,表明配方依赖的PK调节.
结论:
- 定制的脂质体系统可以有效调节和改善各种双价PROTAC分子的血度.
- 在PROTAC-in-cyclodextrin脂酶体系统显示了增强脂友性PROTACs的PK配置文件的希望.
- 对脂质体配方的进一步优化可以改善瘤度和治疗指数,促进新型PROTACs的临床转化.
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