Cinchona Alkaloid Polymers Demonstrate Highly Efficient Gene Delivery Dependent on Stereochemistry, Methoxy Substitution, and Length

Nucleic acid delivery with cationic polymers is a promising alternative to expensive viral-based methods; however, it often suffers from a lower performance. Herein, we present a highly efficient delivery system based on cinchona alkaloid natural products copolymerized with 2-hydroxyethyl acrylate....

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Veröffentlicht in:Biomacromolecules 2024-01, Vol.25 (1), p.486-501
Hauptverfasser: Kreofsky, Nicholas W., Roy, Punarbasu, Brown, Mary E., Perez, Ulises, Leighton, Ryan E., Frontiera, Renee R., Reineke, Theresa M.
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container_end_page 501
container_issue 1
container_start_page 486
container_title Biomacromolecules
container_volume 25
creator Kreofsky, Nicholas W.
Roy, Punarbasu
Brown, Mary E.
Perez, Ulises
Leighton, Ryan E.
Frontiera, Renee R.
Reineke, Theresa M.
description Nucleic acid delivery with cationic polymers is a promising alternative to expensive viral-based methods; however, it often suffers from a lower performance. Herein, we present a highly efficient delivery system based on cinchona alkaloid natural products copolymerized with 2-hydroxyethyl acrylate. Cinchona alkaloids are an attractive monomer class for gene delivery applications, given their ability to bind to DNA via both electrostatics and intercalation. To uncover the structure–activity profile of the system, four structurally similar cinchona alkaloids were incorporated into polymers: quinine, quinidine, cinchonine, and cinchonidine. These polymers differed in the chain length, the presence or absence of a pendant methoxy group, and stereochemistry, all of which were found to alter gene delivery performance and the ways in which the polymers overcome biological barriers to transfection. Longer polymers that contained the methoxy-bearing cinchona alkaloids (i.e., quinine and quinidine) were found to have the best performance. These polymers exhibited the tightest DNA binding, largest and most abundant DNA–polymer complexes, and best endosomal escape thanks to their increased buffering capacity and closest nuclear proximity of the payload. Overall, this work highlights the remarkable efficiency of polymer systems that incorporate cinchona alkaloid natural products while demonstrating the profound impact that small structural changes can have on overcoming biological hurdles associated with gene delivery.
doi_str_mv 10.1021/acs.biomac.3c01099
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