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阳离子聚天冬氨酸衍生物的疏水性调变用于增强反义寡核苷酸递药。

Hydrophobicity Tuning of Cationic Polyaspartamide Derivatives for Enhanced Antisense Oligonucleotide Delivery.

机构信息

Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.

Nucleotide and Peptide Drug Discovery Center (TIDE Center), Institute of Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-0034, Japan.

出版信息

Bioconjug Chem. 2024 Feb 21;35(2):125-131. doi: 10.1021/acs.bioconjchem.3c00456. Epub 2024 Jan 30.

DOI:10.1021/acs.bioconjchem.3c00456
PMID:38290165
Abstract

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, log, of PAsp(DET/R), revealing that the gene knockdown efficiency was substantially improved by PAsp(DET/R) with log 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 log 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 and .

摘要

各种阳离子聚合物被用于递送多聚物介导的反义寡核苷酸 (ASO)。然而，很少有研究探讨多聚物功能的结构决定因素。本研究集中于聚合物的疏水性。一系列具有不同疏水性 (R) 部分的两亲性聚天冬酰胺衍生物，以及带有阳离子二亚乙基三胺 (DET) 部分的侧链 (PAsp(DET/R)s) 被合成，以优化用于锁核酸 (LNA) 间隙寡核苷酸 (ASO) 递送的 R 部分 (或疏水性)。PAsp(DET/R)多聚物的基因敲低效率与 PAsp(DET/R)的疏水性参数 log 作图，结果表明，log 高于-2.4 的 PAsp(DET/R)显著提高了基因敲低效率。这可以通过增加多聚物的稳定性和改善 ASO 有效载荷的细胞摄取来解释。经气管内给药后，与疏水性较低的对照物和裸 ASO 相比，log 高于-2.4 的多聚物样品在肺组织中诱导了更高的基因敲低。这些结果表明，PAsp(DET/R)的疏水性对于有效的 ASO 递送至关重要。

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