title: The Influence of Block Ionomer Microstructure on Polyplex Properties: Can Simulations Help to Understand Differences in Transfection Efficiency?
abstract: Gene therapies enable therapeutic interventions at gene transcription and translation level, providing enormous potential to improve standards of care for multiple diseases. Nonviral transfection agents and in particular polyplexes based on block ionomers are-besides viral vectors and cationic lipid formulations-among the most promising systems for this purpose. Block ionomers combine a hydrophilic noncharged block, e.g., polyethylene glycol (PEG), with a hydrophilic cationic block. For efficient transfection, however, endosomolytic moieties, e.g., imidazoles, are additionally required to facilitate endosomal escape, which raises the general question how to distribute these functionalities within the block copolymer. Combining molecular dynamics simulation with physicochemical and biological characterization, this work aims to provide a first rational for the influence of block ionomer microstructure on polyplex properties, e.g., size, shape, and transfection efficiency. Our findings underline that a triblock microstructure is most efficient in compacting pDNA, which reduces polyplex size, enhances stability against degradation by DNase I, and thus provides better transfection performance.
authors.affiliation: Graduate School Materials Science in Mainz, Johannes Gutenberg University, Staudingerweg 9, 55128, Mainz, Germany.|Institute of Organic Chemistry, Johannes Gutenberg University, Duesbergweg 10-14, 55099, Mainz, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Heller
authors.affiliation: School of Chemistry and Environment, Center of Soft Matter Physics and Its Applications, Beihang University, Xueyuan Road 37, Beijing, 100191, China.
authors.forename: Jiajia
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Institute of Organic Chemistry, Johannes Gutenberg University, Duesbergweg 10-14, 55099, Mainz, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Weber
authors.affiliation: Department of Dermatology, Johannes Gutenberg University Medical Center, Langenbeckstr. 1, 55131, Mainz, Germany.
authors.forename: Dominika
authors.initials: D
authors.lastname: Hobernik
authors.affiliation: Department of Dermatology, Johannes Gutenberg University Medical Center, Langenbeckstr. 1, 55131, Mainz, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Bros
authors.affiliation: Institute of Physics, Johannes Gutenberg University Mainz, Staudingerweg 9, 55099, Mainz, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Schmid
authors.affiliation: Institute of Organic Chemistry, Johannes Gutenberg University, Duesbergweg 10-14, 55099, Mainz, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Barz
keywords: gene therapy; molecular dynamics simulation; polyplex; transfection