National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, China.
College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310014, China.
Int J Mol Sci. 2022 Apr 30;23(9):5014. doi: 10.3390/ijms23095014.
Polyethylenimine (PEI) has been widely used in gene delivery. However, its high cytotoxicity and undesired non-specific protein adsorption hinder the overall delivery efficacy and the practical applications of PEI-based gene delivery systems. In this study, we prepared hydrophobically modified PEIs (H-PEIs) via the reaction of octanal with 40% of primary amines in PEI and PEI, respectively. Two common zwitterionic molecules, 1,3-propanesultone and β-propiolactone, were then used for the modification of the resulting H-PEIs to construct polycationic gene carriers with zwitterionic properties (H-zPEIs). The siRNA delivery efficiency and cytotoxicity of these materials were evaluated in Hela-Luc and A549-Luc cell lines. Compared with their respective parental H-PEIs, different degrees of zwitterionic modification showed different effects in reducing cytotoxicity and delivery efficiency. All zwitterion-modified PEIs showed excellent siRNA binding capacity, reduced nonspecific protein adsorption, and enhanced stability upon nuclease degradation. It is concluded that zwitterionic molecular modification is an effective method to construct efficient vectors by preventing undesired interactions between polycationic carriers and biomacromolecules. It may offer insights into the modification of other cationic carriers of nucleic acid drugs.
聚亚乙基亚胺（PEI）已被广泛应用于基因传递。然而，其高细胞毒性和不理想的非特异性蛋白质吸附会阻碍 PEI 基基因传递系统的整体传递效率和实际应用。在本研究中，我们通过辛醛与 PEI 和 PEI 中 40%的伯胺反应，分别制备了疏水性改性的 PEI（H-PEI）。然后，我们使用两种常见的两性离子分子，1,3-丙磺内酯和β-丙内酯，对所得 H-PEI 进行改性，构建具有两性离子性质的聚阳离子基因载体（H-zPEI）。在 Hela-Luc 和 A549-Luc 细胞系中评估了这些材料的 siRNA 传递效率和细胞毒性。与各自的母体 H-PEI 相比，不同程度的两性离子修饰在降低细胞毒性和传递效率方面表现出不同的效果。所有两性离子修饰的 PEI 均表现出优异的 siRNA 结合能力、减少非特异性蛋白质吸附和增强对核酸酶降解的稳定性。综上所述，两性离子分子修饰是通过防止聚阳离子载体与生物大分子之间的不良相互作用来构建高效载体的有效方法。这可能为修饰其他核酸药物的阳离子载体提供思路。
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