Journal
BIOMATERIALS
Volume 33, Issue 28, Pages 6868-6876Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2012.06.020
Keywords
mRNA; Gene therapy; Copolymer; Micelle; Immune response
Funding
- National Institutes of Health [R01AI074661]
- NIH [EB2991]
- Center for the Intracellular Delivery of Biologics
- Washington State Life Science Discovery Fund [2496490]
- National Science Foundation Graduate Research Fellowship [DGE-0718124]
- Department of Defense through the National Defense Science and Engineering Graduate Fellowship Program
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Messenger RNA (mRNA) is a promising alternative to plasmid DNA (pDNA) for gene vaccination applications, but safe and effective delivery systems are rare. Reversible addition-fragmentation chain transfer (RAFT) polymerization was employed to synthesize a series of triblock copolymers designed to enhance the intracellular delivery of mRNA. These materials are composed of a cationic dimethylaminoethyl methacrylate (DMAEMA) segment to mediate mRNA condensation, a hydrophilic poly(ethylene glycol) methyl ether methacrylate (PEGMA) segment to enhance stability and biocompatibility, and a pH-responsive endosomolytic copolymer of diethylaminoethyl methacrylate (DEAEMA) and butyl methacrylate (BMA) designed to facilitate cytosolic entry. The blocking order and PEGMA segment length were systematically varied to investigate the effect of different polymer architectures on mRNA delivery efficacy. These polymers were monodisperse, exhibited pH-dependent hemolytic activity, and condensed mRNA into 86-216 nm particles. mRNA polyplexes formed from polymers with the PEGMA segment in the center of the polymer chain displayed the greatest stability to heparin displacement and were associated with the highest transfection efficiencies in two immune cell lines, RAW 264.7 macrophages (77%) and DC2.4 dendritic cells (50%). Transfected DC2.4 cells were shown to be capable of subsequently activating antigen-specific T cells, demonstrating the potential of these multifunctional triblock copolymers for mRNA-based vaccination strategies. (C) 2012 Elsevier Ltd. All rights reserved.
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