基因传递的增强生物相容性基于树突基因的基因传递通过histidine修饰的核定位信号
Jeil Lee1, Yong-Eun Kwon2, Seth D Edwards1
1Department of Chemical Engineering, University of New Hampshire, Durham, New Hampshire 03824, United States.
International journal of pharmaceutics
|August 9, 2023
概括
将histidine添加到核定位信号 (NLS) 修饰的聚胺胺 (PAMAM) 树状体中,通过清除活性氧物种 (ROS) 来降低细胞毒性. 这种histidine修饰可以提高基因传递的安全性,而不会影响转染效率.
科学领域:
- 生物材料科学 生物材料科学
- 纳米技术 纳米技术
- 基因传递系统是基因传递系统.
背景情况:
- 聚胺胺 (PAMAM) 树枝状体是有前途的基因传递载体,由于其低细胞毒性和生物相容性.
- 核定位信号 (NLS) 增强树枝状体传染效率,但可以通过活性氧物种 (ROS) 增加细胞毒性.
- 希斯蒂丁是一种天然抗氧化剂,可以减轻树枝状细胞体中NLS诱导的细胞毒性.
研究的目的:
- 调查希斯蒂丁降低NLS修饰的PAMAM树状体细胞毒性的机制.
- 为了合成和表征NLS修饰的囊胺核PAMAM树突基2代 (cPG2) 具有不同的histidine结合.
- 为了评估希斯提丁结合对转染效率和细胞毒性的影响.
主要方法:
- 合成与NLS结合的cPG2树脂分子与0-3胺残留物.
- 对NIH3T3和人类介质干细胞 (hMSC) 转染效率的评估与PEI 25 kDa相比.
- 使用HORAC和DCFDA试验评估细胞毒性和ROS清除活性.
- 使用JC-1光成像进行线粒体膜潜能评估.
主要成果:
- 经过NLS修改的cPG2树突体表现出与PEI 25 kDa相比或更高的转化效率.
- 细胞毒性明显低于PEI 25 kDa,并且随着胺含量增加而降低.
- 希斯蒂丁结合增强了ROS清理能力,并保护了线粒体膜潜力.
- 观察到细胞内氧基度降低与增加的histidine数量.
结论:
- 希斯蒂丁结合有效地通过清除ROS.通过减少NLS修饰的树突细胞毒性.
- 含有histidine的NLS-dendrimers提供了一个更安全,更有效的基因传递平台.
- 这项研究阐明了histidine在NLS-dendrimer基因传递中的细胞保护机制.
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