The unique molecular structure confers the diquaternary ammonium gemini surfactants with enhanced nucleic acid complexation ability, bottom-up design flexibility, and relatively low cytotoxicity. To capitalize on their potential as gene delivery vectors, novel structural modifications should be explored. In this work, 22 novel peptide-modified gemini surfactants with various alkyl tails and peptide spacer modifications were evaluated. This work represents the first report of dendrimer-like gemini surfactants and first evaluation of the impact of incorporating a hydrocarbon linker into the peptide chain. Our aim was to establish a structure activity relationship of the peptide-modified gemini surfactants and to identify the fundamental architectural requirements needed for the ultimate gene delivery systems. In vitro assessment revealed that the highest transfection efficiency and lowest cytotoxicity were associated with the glycyl-lysine modified gemini surfactants having the hexadecyl tail, 16-7N(G-K)-16. In fact, it showed an 8-fold increase in secreted protein with 20% increase in cell viability relative to the first-generation unsubstituted gemini surfactants. Further increase in the size of the attached peptides resulted in a decrease in the transfection efficiency and cell viability. Whereas the incorporation of a hydrocarbon linker into the peptide chain decreased the transfection efficiency of compounds with dipeptides, it increased the transfection efficiency of compounds with larger peptide chains. Such an increase was more prominent with the incorporation of a longer hydrocarbon linker. We conclude that a balance between the hydrophilic and hydrophobic characteristics of the compound is necessary since it results in physicochemical parameters conducive to the gene delivery process.

中文翻译：

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分子工程作为调节肽修饰的双子表面活性剂基因传递效率的一种方法

独特的分子结构使双季铵盐双子表面活性剂具有增强的核酸络合能力，自下而上的设计灵活性和相对较低的细胞毒性。为了利用它们作为基因传递载体的潜力，应该探索新的结构修饰。在这项工作中，评估了22种具有各种烷基尾部和肽间隔基修饰的新型肽改性双子表面活性剂。这项工作代表了树状大分子双子表面活性剂的首次报道，并且首次评估了将烃类连接基引入肽链的影响。我们的目的是建立肽修饰的双子表面活性剂的结构活性关系，并确定最终基因递送系统所需的基本结构要求。体外评估显示，最高转染效率和最低细胞毒性与具有十六烷基尾巴16-7N（GK）-16的甘氨酰赖氨酸修饰的双子表面活性剂有关。实际上，与第一代未取代的双子表面活性剂相比，它的分泌蛋白增加了8倍，而细胞活力却提高了20％。附着肽大小的进一步增加导致转染效率和细胞生存力降低。尽管将烃连接基掺入肽链降低了具有二肽的化合物的转染效率，但是却增加了具有较大肽链的化合物的转染效率。随着更长的烃连接基的引入，这种增加更加显着。