基于高级层次计算建模的 (II) 纳米复合物的合理开发,以改善肺癌治疗
Haozhe Huang1,2,3, Beihong Ji4,3, Yixian Huang1,2
1Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
概括
癌症干细胞 (CSC) 中的化疗耐药性可以通过同时阻断AKT1和COX-2通路来克服. 一种新型的纳米载体提供西斯,AKT1抑制剂和COX-2抑制剂,减少瘤负担并增强肺癌治疗.
科学领域:
- 在瘤学瘤学.
- 癌症生物学 癌症生物学
- 纳米医学是一种纳米医学.
背景情况:
- 癌症干细胞 (CSCs) 驱动治疗耐药性和瘤复发.
- 在化疗期间产生CSC的重编程网络仍然不清楚.
- 西斯丁 (CDDP) 治疗通过鲜为人知的机制丰富了CSC.
研究的目的:
- 阐明由CDDP诱导的CSC丰富机制.
- 确定针对肺癌中CSC的治疗策略.
- 开发一种用于组合治疗的新型药物输送系统.
主要方法:
- 生物信息学分析以确定CSC丰富途径.
- 计算建模 (分子对接,MD模拟,结合自由能分析) 来选择抑制剂.
- 开发一种由5-ASA衍生的双功能免疫刺激纳米载体 (PASA) 用于代码交付.
- 在体内研究中,使用了正原体和转移性肺癌模型.
主要成果:
- 通过激活AKT1通路,CDDP治疗丰富了CSCs,并通过COX-2信号进一步增强了它.
- 同时阻断AKT1和COX-2可以协同减少CSCs.
- 一种三重组合疗法 (PASA/CDDP/MK-2206) 显著降低了瘤负担.
- 组合疗法消除了CSC并逆转了免疫抑制瘤微环境.
结论:
- 准AKT1和COX-2通路是对抗CSC驱动的化学抵抗的一种有希望的策略.
- PASA/CDDP/MK-2206组合疗法为肺癌治疗提供了一个潜在的新方法.
- 逆转CSC和瘤微环境是克服肺癌化学抵抗的关键.
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