聚乙烯亚胺（PEI）是一种高效的正电聚合物，可用于核酸传递，尽管它在临床前研究中常用，但其临床应用受到其细胞毒性的限制。聚（β-氨酸酯）是一类新型可降解和生物相容性的正电聚合物，可用于siRNA传递。在本研究中，我们基于亚精胺和1,4-丁二醇二丙烯酸酯合成了保护和脱保护的聚（β-氨酸酯），分别命名为P(BSpBAE)和P(SpBAE)，用于siRNA传递。通过Michael加成反应和步步生长聚合合成了这些聚合物，并通过1H核磁共振波谱和分子尺寸排阻层析进行了表征。通过SYBR gold实验，证明这些聚合物可以封装siRNA。这两种聚合物和聚物复合物在体外均表现出生物相容性。此外，与相同N/P比例下的分支PEI（25 kDa）聚物复合物相比，P(BSpBAE)和P(SpBAE)聚物复合物的细胞摄取效率更高。P(BSpBAE)聚物复合物在体外实现了60%的eGFP沉默，这表明Boc保护可以改善PBAEs的siRNA传递和基因沉默效率。P(BSpBAE)聚物复合物和P(SpBAE)聚物复合物显示了不同的细胞摄取机制，并且P(BSpBAE)聚物复合物表现出较少的内体捕获，这可能解释了为什么P(BSpBAE)聚物复合物比P(SpBAE)聚物复合物更有效地介导基因沉默。此外，对KRAS突变肺癌细胞转染突变KRAS的siRNA，P(BspBAE)和P(SpBAE)的抗体共治疗体外实现了约35%（P(BSpBAE)）到45%（P(SpBAE)）的KRAS表达抑制和约33%（P(SpBAE)）到55%（P(BspBAE)）的迁移能力降低。这些结果表明，新开发的以亚精胺为基础的聚（β-氨酸酯）是治疗性siRNA传递的有前途的材料。

Polyethylenimine (PEI) is a highly efficient cationic polymer for nucleic acid delivery, and although it is commonly used in preclinical studies, its clinical application is limited because of concerns regarding its cytotoxicity. Poly(β-amino ester)s are a new group of biodegradable and biocompatible cationic polymers that can be used for siRNA delivery. In this study, we synthesized Boc-protected and deprotected poly(β-amino ester)s, P(BSpBAE) and P(SpBAE), respectively, based on spermine and 1,4-butanediol diacrylate to deliver siRNA. The polymers were synthesized by Michael addition in a step-growth polymerization and characterized via 1H NMR spectroscopy and size-exclusion chromatography (SEC). The polymers can encapsulate siRNA as determined by SYBR gold assays. Both polymers and polyplexes were biocompatible in vitro. Furthermore, the cellular uptake of P(BSpBAE) and P(SpBAE) polyplexes was more efficient than for branched PEI (25 kDa) polyplexes at the same N/P ratios. P(BSpBAE) polyplexes achieved 60% eGFP knockdown in vitro, which indicates that the Boc-protection can improve the siRNA delivery and gene silencing efficiency of PBAEs. P(BSpBAE) polyplexes and P(SpBAE) polyplexes showed different cellular uptake mechanisms, and P(BSpBAE) polyplexes demonstrated decreased endosomal entrapment, which could explain why P(BSpBAE) polyplexes more efficiently mediated gene silencing than P(SpBAE) polyplexes. Furthermore, transfection of an siRNA against mutated KRAS in KRAS-mutated lung cancer cells led to around 35% (P(BspBAE)) to 45% (P(SpBAE)) inhibition of KRAS expression and around 33% (P(SpBAE)) to 55% (P(BspBAE)) decreased motility in a migration assay. These results suggest that the newly developed spermine-based poly(β-amino ester)s are promising materials for therapeutic siRNA delivery.