When optimizing nanocarriers, structural motifs that are beneficial for the respective type of cargo need to be identified. Here, succinoyl tetraethylene pentamine (Stp)-based lipo-oligoaminoamides (OAAs) were optimized for the delivery of plasmid DNA (pDNA). Structural variations comprised saturated fatty acids with chain lengths between C2 and C18 and terminal cysteines as units promoting nanoparticle stabilization, histidines for endosomal buffering, and disulfide building blocks for redox-sensitive release. Biophysical and tumor cell culture screening established clear-cut relationships between lipo-OAAs and characteristics of the formed pDNA complexes. Based on the optimized alternating Stp-histidine backbones, lipo-OAAs containing fatty acids with chain lengths around C6 to C10 displayed maximum gene transfer with around 500-fold higher gene expression than that of C18 lipo-OAA analogues. Promising lipo-OAAs, however, showed only moderate in vivo efficiency. In vitro testing in 90% full serum, revealing considerable inhibition of lytic and gene-transfer activity, was found as a new screening model predictive for intravenous applications in vivo.

中文翻译：

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优化 pDNA 脂质复合物：稳定性和货物释放之间的平衡行为

在优化纳米载体时，需要确定对相应类型货物有益的结构基序。在这里，基于琥珀酰四亚乙基五胺 (Stp) 的脂低聚氨基酰胺 (OAAs) 被优化用于质粒 DNA (pDNA) 的递送。结构变化包括链长在 C2 和 C18 之间的饱和脂肪酸和末端半胱氨酸作为促进纳米颗粒稳定的单位、用于内体缓冲的组氨酸和用于氧化还原敏感释放的二硫化物构件。生物物理和肿瘤细胞培养筛选在 lipo-OAAs 与形成的 pDNA 复合物的特征之间建立了明确的关系。基于优化的交替 Stp-组氨酸骨架，含有链长在 C6 到 C10 左右的脂肪酸的 lipo-OAA 显示出最大的基因转移，其基因表达比 C18 lipo-OAA 类似物高约 500 倍。然而，有希望的 lipo-OAAs 仅表现出中等体内效率。在90% 全血清中进行体外测试，揭示了对裂解和基因转移活性的显着抑制，被发现是一种预测体内静脉应用的新筛选模型。