Abstract
The controlled release of nucleic acids from cationic polymers is an important criteria for the design of gene delivery systems, and can be difficult to achieve due to the persistent positive charges required to initially complex the nucleic acids. Here, we report the use of highly branched tertiary amine-rich polymers for the complexation and release of dsRNA over a prolonged period of time. Controlled release of dsRNA is obtained via self-catalysed hydrolysis of the polymer side chains and associated change in electrostatic charge. Reversible addition-fragmentation chain transfer (RAFT) polymerization was utilised to synthesise a series of branched polymers of 2-(dimethylamino)ethyl acrylate (DMAEA), 3-(dimethylamino)propyl acrylate (DMAPA), and 2-(dimethylamino)ethyl methacrylate (DMAEMA) (MW ∼60000-200000 g mol-1) and copolymers thereof. The hydrolysis kinetics of all synthesised polymer materials were followed by 1H NMR spectroscopy. Complexation with dsRNA resulted in the formation of polyplex nanoparticles (N/P ratio of 5) with sizes of approximately 400 nm and surface charges of +15 mV. An agarose gel retardation assay showed sustained release of dsRNA from p(DMAEA-co-DMAEMA) for a period of more than 2 weeks. Unlike branched PEI commonly used for gene delivery, the majority of these systems showed little toxicity to cells (NIH3T3 fibroblasts). The results point towards pDMAPA and p(DMAEA-co-DMAEMA) being promising polymers for the controlled release of nucleic acids over prolonged periods.
| Original language | English |
|---|---|
| Pages (from-to) | 4025-4035 |
| Number of pages | 11 |
| Journal | Polymer Chemistry |
| Volume | 9 |
| Issue number | 29 |
| DOIs | |
| Publication status | Published - 7 Aug 2018 |
| Externally published | Yes |
Bibliographical note
Funding Information:The Royal Society Wolfson Merit Award (WM130055; S. P.), Monash-Warwick Alliance (S. P.), and Syngenta (A. C., R. W.) are acknowledged for financial support. The European Research Council (TUSUPO 647106; S. P., R. P.) and the German Research Foundation (DFG, GZ: HA 7725/1-1; M. H.) are gratefully acknowledged for funding. The authors would like to thank Dr Daniel Lester and the University of Warwick Polymer Characterisation Research Technology Platform (RTP) for use of GPC facilities.
Publisher Copyright:
© 2018 The Royal Society of Chemistry.
Funding
The Royal Society Wolfson Merit Award (WM130055; S. P.), Monash-Warwick Alliance (S. P.), and Syngenta (A. C., R. W.) are acknowledged for financial support. The European Research Council (TUSUPO 647106; S. P., R. P.) and the German Research Foundation (DFG, GZ: HA 7725/1-1; M. H.) are gratefully acknowledged for funding. The authors would like to thank Dr Daniel Lester and the University of Warwick Polymer Characterisation Research Technology Platform (RTP) for use of GPC facilities.