Various cationic polymers are used to deliver polyplex-mediated antisense oligonucleotides (ASOs). However, few studies have investigated the structural determinants of polyplex functionalities in polymers. This study focused on the polymer hydrophobicity. A series of amphiphilic polyaspartamide derivatives possessing various hydrophobic (R) moieties together with cationic diethylenetriamine (DET) moieties in the side chain (PAsp(DET/R)s) were synthesized to optimize the R moieties (or hydrophobicity) for locked nucleic acid (LNA) gapmer ASO delivery. The gene knockdown efficiencies of PAsp(DET/R) polyplexes were plotted against a hydrophobicity parameter, logD_7.3, of PAsp(DET/R), revealing that the gene knockdown efficiency was substantially improved by PAsp(DET/R) with logD_7.3 higher than −2.4. This was explained by the increased polyplex stability and improved cellular uptake of ASO payloads. After intratracheal administration, the polyplex samples with a higher logD_7.3 than −2.4 induced a significantly higher gene knockdown in the lung tissue compared with counterparts with lower hydrophobicity and naked ASO. These results demonstrate that the hydrophobicity of PAsp(DET/R) is crucial for efficient ASO delivery in vitro and in vivo.

中文翻译：

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阳离子聚天冬酰胺衍生物的疏水性调节以增强反义寡核苷酸递送

各种阳离子聚合物用于递送复合物介导的反义寡核苷酸（ASO）。然而，很少有研究调查聚合物中复合物官能团的结构决定因素。本研究的重点是聚合物的疏水性。合成了一系列具有各种疏水性 (R) 部分以及侧链中的阳离子二亚乙基三胺 (DET) 部分的两亲性聚天冬酰胺衍生物 (PAsp(DET/R)s)，以优化锁核酸的 R 部分（或疏水性）。 LNA）gapmer ASO 交付。将 PAsp(DET/R) 复合物的基因敲低效率与 PAsp(DET/R) 的疏水性参数 log D _7.3作图，表明 PAsp(DET/R) 显着提高了基因敲低效率，log D _7.3高于-2.4。这是由于复合物稳定性的增加和 ASO 有效负载的细胞吸收的改善所致。气管内给药后，与疏水性较低和裸 ASO 的对应物相比，log D _7.3高于 -2.4的复合物样品在肺组织中诱导显着更高的基因敲低。这些结果表明 PAsp(DET/R) 的疏水性对于体外和体内ASO 的有效递送至关重要。