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

Overview

Journal ACS Macro Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2024 Jul 25

PMID 39052525

Authors

Prosper P Mapfumo

Lien S Reichel

Katharina Leer

Jan Egger

Andreas Dzierza

Kalina Peneva

Dagmar Fischer

Anja Traeger

Affiliations

Soon will be listed here.

Abstract

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 -acryloyl-l-histidine (His) monomer was systematically increased, while maintaining consistent levels of methyl -acryloyl-l-argininate hydrochloride (ArgOMe) or -(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.

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