title: Reductive Decationizable Block Copolymers for Stimuli-Responsive mRNA Delivery.
abstract: Messenger ribonucleic acids (mRNAs) are considered as promising alternatives for transient gene therapy, but to overcome their poor pharmacokinetic properties, smart carriers are required for cellular uptake and stimuli-responsive release. In this work, a synthetic concept toward reductive decationizable cationic block copolymers for mRNA complexation is introduced. By combination of RAFT block copolymerization with postpolymerization modification, cationic block copolymers are generated with disulfide-linked primary amines. They allow effective polyplex formation with negatively charged mRNA and subsequent release under reductive conditions of the cytoplasm. In first in vitro experiments with fibroblasts and macrophages, tailor-made block copolymers mediate cell-specific mRNA transfection, as quantified by polyplex uptake and mRNA-encoding gene expression. Furthermore, RAFT polymerization provides access to heterotelechelic polymers with orthogonally addressable endgroup functionalities utilized to ligate targeting units onto the polyplex-forming block copolymers. The results exemplify the broad versatility of this reductive decationizable mRNA carrier system, especially toward further advanced mRNA delivery applications.
authors.affiliation: Institute of Organic Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 10-14, D-55099, Mainz, Germany.|Department of Pharmaceutics, Ghent University, Ottergemsesteenweg 460, B-9000, Ghent, Belgium.
authors.forename: Lutz
authors.initials: L
authors.lastname: Nuhn
authors.affiliation: Institute of Translational Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstraße 1, D-55101, Mainz, Germany.
authors.forename: Leonard
authors.initials: L
authors.lastname: Kaps
authors.affiliation: TRON - Translational Oncology, University Medical Center of the Johannes Gutenberg-University Mainz, Freiligrathstraße 12, D-55131, Mainz, Germany.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Diken
authors.affiliation: Institute of Translational Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstraße 1, D-55101, Mainz, Germany.|Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA.
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
authors.affiliation: Institute of Organic Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 10-14, D-55099, Mainz, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zentel
mesh_terms: D016475:3T3 Cells; D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods*; D051379:Mice; D011108:Polymers / Q000737:chemistry* / Q000494:pharmacology*; D012333:RNA, Messenger / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D011108:Polymers; D012333:RNA, Messenger
keywords: RAFT polymerization; SPAAC; mRNA delivery; polyplexes; stimuli-responsiveness