A cationic, dendrimer-like oligo(aminoamide) carrier with four-arm topology based on succinoyl tetraethylene pentamine and histidines, cysteines, and N-terminal azido-lysines was screened for plasmid DNA delivery on various cell lines. The incorporated azides allow modification with various shielding agents of different polyethylene glycol (PEG) lengths and/or different ligands by copper-free click reaction, either before or after polyplex formation. Prefunctionalization was found to be advantageous over postfunctionalization in terms of nanoparticle formation, stability, and efficacy. A length of 24 ethylene oxide repetition units and prefunctionalization of ≥50% of azides per carrier promoted optimal polyplex shielding. PEG shielding resulted in drastically reduced DNA transfer, which could be successfully restored by active lectin targeting via novel GalNAc or mannose ligands, enabling enhanced receptor-mediated endocytosis of the carrier system. The involvement of the asialoglycoprotein receptor (ASGPR) in the uptake of GalNAc-functionalized polyplexes was confirmed in the ASGPR-positive hepatocarcinoma cell lines HepG2 and Huh7. Mannose-modified polyplexes showed superior cellular uptake and transfection efficacy compared to unmodified and shielded polyplexes in mannose-receptor-expressing dendritic cell-like DC2.4 cells.

中文翻译：

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GalNAc 或甘露糖 PEG 功能化复合物可实现有效的凝集素介导的 DNA 递送

筛选了一种基于琥珀酰四亚乙基五胺和组氨酸、半胱氨酸和N端叠氮基赖氨酸的四臂拓扑结构的阳离子树枝状寡聚（氨基酰胺）载体，用于在各种细胞系上递送质粒 DNA。掺入的叠氮化物允许在复合物形成之前或之后通过无铜点击反应用不同聚乙二醇（PEG）长度和/或不同配体的各种屏蔽剂进行修饰。研究发现，在纳米颗粒形成、稳定性和功效方面，预官能化优于后官能化。 24 个环氧乙烷重复单元的长度和每个载体 ≥50% 叠氮化物的预官能化促进了最佳的聚合屏蔽。 PEG屏蔽导致DNA转移大大减少，这可以通过新型GalNAc或甘露糖配体的活性凝集素靶向成功地恢复，从而增强载体系统的受体介导的内吞作用。在 ASGPR 阳性肝癌细胞系 HepG2 和 Huh7 中证实了脱唾液酸糖蛋白受体 (ASGPR) 参与 GalNAc 功能化复合物的摄取。与未修饰和屏蔽的多聚复合物相比，甘露糖修饰的多聚复合物在表达甘露糖受体的树突状细胞样DC2.4细胞中表现出优异的细胞摄取和转染功效。