Polymeric materials provide particularly attractive scaffolds for the creation of supramolecular bioconjugates for the delivery of nucleic acids but typically lack the efficiency and biocompatibility to be clinically relevant. To address both issues, we produced zwitterion-like derivatives of polyethylenimine via succinylation of primary and secondary amines (zPEI). Polymers were generated with 9–55% of the amines modified (zPEI X, where X indicates the percentage of amines succinylated). Characterization of polymer/DNA interactions revealed that the presence of succinyl groups decreased the protonation constant of zPEI, resulting in both a decreased buffering capacity and polyplexes that dissociated in the presence of lower amounts of a competing counteranion compared to unmodified PEI. zPEI polyplexes also exhibited decreased aggregation in the presence of serum proteins. In the absence of serum, transfections with zPEI/DNA polyplexes exhibited similar or slightly improved transgene expression compared to unmodified PEI/DNA polyplexes. More importantly, zPEI 9–25 increased transgene expression up to 51-fold upon transfection in the presence of serum compared to PEI/DNA, while higher succinylation decreased gene delivery activity. Gene delivery mediated by zPEI 9/DNA polyplexes in the presence of serum was equal to or greater than unmodified PEI/DNA polyplexes in the absence of serum. The data suggest that succinylation increased gene transfection by decreasing polymer/DNA interaction strength, which may allow for more facile polyplex unpackaging, and/or increased stability of polyplex size and inhibition of aggregation in the presence of serum. However, it appears there exists a balance between the positive effects of succinylation and the need for sufficient polymer/DNA binding to condense and protect the cargo.

中文翻译：

---

琥珀酰化聚乙烯亚胺衍生物极大地增强了多聚体血清的稳定性和体外基因传递。

聚合材料为产生用于递送核酸的超分子生物缀合物提供了特别有吸引力的支架，但是通常缺乏与临床相关的效率和生物相容性。为了解决这两个问题，我们通过伯胺和仲胺（zPEI）的琥珀酰化反应生产了聚乙烯亚胺的两性离子样衍生物。生成的聚合物具有9–55％的胺改性（zPEI X，其中X表示琥珀酰化胺的百分比）。聚合物/ DNA相互作用的表征表明，琥珀酰基团的存在降低了zPEI的质子化常数，与未修饰的PEI相比，缓冲容量降低，并且在存在较少量竞争性抗衡阴离子的情况下解离的多聚体都消失了。在血清蛋白存在下，zPEI多聚体也表现出降低的聚集。在没有血清的情况下，与未修饰的PEI / DNA多聚体相比，zPEI / DNA多聚体的转染表现出相似或略有改善的转基因表达。更重要的是，与PEI / DNA相比，在有血清的情况下转染后，zPEI 9-25可使转基因表达增加多达51倍，而更高的琥珀酰化作用会降低基因传递活性。在存在血清的情况下，由zPEI 9 / DNA复合物介导的基因传递等于或大于在不存在血清的情况下未修饰的PEI / DNA复合物。数据表明，琥珀酰化通过降低聚合物/ DNA相互作用强度来增加基因转染，这可能使多态复合物更容易拆包，和/或多态复合物尺寸的稳定性增加，并在存在血清的情况下抑制聚集。然而，似乎在琥珀酰化的积极作用与需要足够的聚合物/ DNA结合以凝缩和保护货物之间存在平衡。这可以允许更容易的多聚体解包装，和/或在血清存在下多聚体尺寸的稳定性增加和聚集的抑制。然而，似乎在琥珀酰化的积极作用与需要足够的聚合物/ DNA结合以凝缩和保护货物之间存在平衡。这可以允许更容易的多聚体解包装，和/或在血清存在下多聚体尺寸的稳定性增加和聚集的抑制。然而，似乎在琥珀酰化的积极作用与需要足够的聚合物/ DNA结合以凝缩和保护货物之间存在平衡。