A Low Protein Binding Cationic Poly(2-oxazoline) as Non-Viral Vector
KAUST Grant NumberKUK-F1-029-32
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Abstract© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Developing safe and efficient non-viral gene delivery systems remains a major challenge. We present a new cationic poly(2-oxazoline) (CPOx) block copolymer for gene therapy that was synthesized by sequential polymerization of non-ionic 2-methyl-2-oxazoline and a new 2-oxazoline monomer, 2-(N-methyl, N-Boc-amino)-methyl-2-oxazoline, followed by deprotection of the pendant secondary amine groups. Upon mixing with plasmid DNA (pDNA), CPOx forms small (diameter ≈80 nm) and narrowly dispersed polyplexes (PDI <0.2), which are stable upon dilution in saline and against thermal challenge. These polyplexes exhibited low plasma protein binding and very low cytotoxicity in vitro compared to the polyplexes of pDNA and poly(ethylene glycol)-b-poly(L-lysine) (PEG-b-PLL). CPOx/pDNA polyplexes at N/P = 5 bound considerably less plasma protein compared to polyplexes of PEG-b-PLL at the same N/P ratio. This is a unique aspect of the developed polyplexes emphasizing their potential for systemic delivery in vivo. The transfection efficiency of the polyplexes in B16 murine melanoma cells was low after 4 h, but increased significantly for 10 h exposure time, indicative of slow internalization of polyplexes. Addition of Pluronic P85 boosted the transfection using CPOx/pDNA polyplexes considerably. The low protein binding of CPOx/pDNA polyplexes is particularly interesting for the future development of targeted gene delivery.
CitationHe Z, Miao L, Jordan R, S-Manickam D, Luxenhofer R, et al. (2015) A Low Protein Binding Cationic Poly(2-oxazoline) as Non-Viral Vector. Macromolecular Bioscience 15: 1004–1020. Available: http://dx.doi.org/10.1002/mabi.201500021.
SponsorsThis study was supported by the Eshelman Gift Trust funds (to A.V.K), by award no. KUK-F1-029-32, made by King Abdullah University of Science and Technology (KAUST), by the Free State of Bavaria, the Fonds der Chemischen Industrie through a junior faculty support grant and start-up funding from the German Plastics Center SKZ and the University of Würzburg (all to R. L.) and partially by the Cancer Nanotechnology Platform Partnership grant (U01 CA116591, to A.V.K) of the National Cancer Institute Alliance for Cancer Nanotechnology. Z. H. is also grateful to GlaxoSmithKline Clinical Research and Drug Development Fellowship support. The authors would like to thank the Chapel Hill Analytical and Nanofabrication Laboratory (CHANL) and Proteomics Core Facility at UNC-CH. The authors also acknowledge technical support from Mr. Matthew Haney for the confocal microscopy, Mr. Yuhang Jiang for the gel electrophoresis, Mr. Vivek Mahajan for the supply of pDNA, and Mr. Jonas F. Nawroth for the monomer synthesis.
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