Harnessing Guanidinium and Imidazole Functional Groups: A Dual-Charged Polymer Strategy for Enhanced Gene Delivery,ACS Macro Letters

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Harnessing Guanidinium and Imidazole Functional Groups: A Dual-Charged Polymer Strategy for Enhanced Gene Delivery
ACS Macro Letters ( IF 5.1 ) Pub Date : 2024-07-25 , DOI: 10.1021/acsmacrolett.4c00321
Prosper P Mapfumo ₁ , Liên S Reichel ₁ , Katharina Leer ₁ , Jan Egger ₂ , Andreas Dzierza ₂ , Kalina Peneva _{1,

3,

4} , Dagmar Fischer _{2,

3,

5} , Anja Traeger _{1,

3}

Affiliation

Histidine and arginine are two amino acids that exhibit beneficial properties for gene delivery. In particular, the imidazole group of histidine facilitates endosomal release, while the guanidinium group of arginine promotes cellular entry. Consequently, a dual-charged copolymer library based on these amino acids was synthesized via reversible addition–fragmentation chain transfer (RAFT) polymerization. The content of the N-acryloyl-l-histidine (His) monomer was systematically increased, while maintaining consistent levels of methyl N-acryloyl-l-argininate hydrochloride (ArgOMe) or N-(4-guanidinobutyl)acrylamide hydrochloride (GBAm). The resulting polymers formed stable, nanosized polyplexes when complexed with nucleic acids. Remarkably, candidates with increased His content exhibited reduced cytotoxicity profiles and enhanced transfection efficiency, particularly retaining this performance level at lower pDNA concentrations. Furthermore, endosomal release studies revealed that increased His content improved endosomal release, while ArgOMe improved cellular entry. These findings underscore the potential of customized dual-charged copolymers and the synergistic effects of His and ArgOMe/GBAm in enhancing gene delivery.

中文翻译：

利用胍和咪唑官能团：增强基因递送的双电荷聚合物策略

组氨酸和精氨酸是两种氨基酸，对基因递送表现出有益的特性。特别是，组氨酸的咪唑基团促进内体释放，而精氨酸的胍基团促进细胞进入。因此，通过可逆加成-碎裂链转移（RAFT）聚合合成了基于这些氨基酸的双电荷共聚物库。N-丙烯酰-l-组氨酸（His）单体的含量系统增加，同时保持 N-丙烯酰-l-精氨酸盐酸甲酯（ArgOMe）或 N-（4-胍基丁基）丙烯酰胺盐酸盐（GBAm）水平一致。当与核酸复合时，所得聚合物形成稳定的纳米级多链体。值得注意的是，His 含量增加的候选药物表现出较低的细胞毒性特征和增强的转染效率，特别是在较低的 pDNA 浓度下保持这一性能水平。此外，内体释放研究表明，增加 His 含量可改善内体释放，而 ArgOMe 可改善细胞进入。这些发现强调了定制的双电荷共聚物的潜力以及 His 和 ArgOMe/GBAm 在增强基因递送方面的协同作用。

更新日期：2024-07-25

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