Tailoring Gene Transfer Efficacy through the Arrangement of Cationic and Anionic Blocks in Triblock Copolymer Micelles

Katharina Leer; Liên S Reichel; Mara Wilhelmi; Johannes C Brendel; Anja Traeger

doi:10.1021/acsmacrolett.3c00633

Tailoring Gene Transfer Efficacy through the Arrangement of Cationic and Anionic Blocks in Triblock Copolymer Micelles

ACS Macro Lett. 2024 Jan 17;13(2):158-165. doi: 10.1021/acsmacrolett.3c00633. Online ahead of print.

Authors

Katharina Leer¹, Liên S Reichel¹, Mara Wilhelmi¹, Johannes C Brendel^{1

2}, Anja Traeger^{1

2}

Affiliations

¹ Laboratory of Organic and Macromolecular Chemistry, Friedrich Schiller University Jena, Humboldtstrasse 10, 07743 Jena, Germany.
² Jena Center for Soft Matter, Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany.

Abstract

The arrangement of charged segments in triblock copolymer micelles affects the gene delivery potential of polymeric micelles and can increase the level of gene expression when an anionic segment is incorporated in the outer shell. Triblock copolymers were synthesized by RAFT polymerzation with narrow molar mass distributions and assembled into micelles with a hydrophobic core from poly(n-butyl acrylate). The ionic shell contained either (i) an anionic segment followed by a cationic segment (HAC micelles) or (ii) a cationic block followed by an anionic block (HCA micelles). The pH-responsive anionic block contained 2-carboxyethyl acrylamide (CEAm), while the cationic block comprised 3-guanidinopropyl acrylamide (GPAm). Increasing the molar content of CEAm in HAC and HCA micelles from 6 to 13 mol % improved cytocompatibility and the endosomal escape property, while the HCA micelle with the highest mol % of anionic charges in the outer shell exhibited the highest gene expression. It became evident that improved membrane interaction of the best performing HCA micelle contributed to achieving high gene expression.