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Joubert, Fanny; Munson, Michael J.; Sabirsh, Alan; England, Richard M.; Hemmerling, Martin; Alexander, Cameron; Ashford, Marianne B.
Journal of controlled release, April 2023, 2023-04-00, 20230401, Letnik: 356Journal Article
Here, we aimed to chemically modify PAMAM dendrimers using lysine as a site-selective anchor for successfully delivering mRNA while maintaining a low toxicity profile. PAMAM dendrimers were multi-functionalised by amidation reactions in a regioselective, quantitative and stepwise manner with carefully selected property-modifying surface groups. Alternatively, novel lysine-based dendrimers were prepared in the same manner with the aim to unlock their potential in gene delivery. The modified dendrimers were then formulated with Cy5-EGFP mRNA by bulk mixing via liquid handling robotics across different nitrogen to phosphate ratios. The resulting dendriplexes were characterised by size, charge, mRNA encapsulation, and mRNA binding affinity. Finally, their in-vitro delivery activity was systematically investigated across key cellular trafficking stages to relate chemical design to cellular effect. We demonstrate our findings in different cell lines and benchmarked relative to a commercially available transfection agent, jetPEI®. We demonstrate that specific surface modifications are required to generate small, reliable and well-encapsulated positively charged dendriplex complexes. Furthermore, we show that introduction of fusogenic groups is essential for driving endosomal escape and achieving cellular delivery and translation of mRNA in these cell lines. Display omitted •PAMAM & lysine dendrimers were modified with functional groups for mRNA delivery•Automated formulation established optimal mRNA cargo loading conditions•In-vitro testing identified dendrimers with improved endosomal escape, particularly by p-toluylsulfonyl arginine groups•Dendrimers outperformed a commercial standard, jetPEI®•Effective dendrimers for mRNA delivery were well tolerated in vitro.
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Leto | Faktor vpliva | Izdaja | Kategorija | Razvrstitev | ||||
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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