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Nucleic Acids Research 2005 33(9):e86; doi:10.1093/nar/gni085
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Published online 24 May 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oupjournals.org

Methods Online

A versatile reducible polycation-based system for efficient delivery of a broad range of nucleic acids

Martin L. Read*, Surjeet Singh1, Zubair Ahmed, Mark Stevenson2, Simon S. Briggs2, David Oupicky3, Lee B. Barrett4, Rachel Spice, Mark Kendall5, Martin Berry, Jon A. Preece1, Ann Logan and Leonard W. Seymour2

Molecular Neuroscience Group, Department of Medicine, University of Birmingham Birmingham, B15 2TT, UK 1School of Chemistry, University of Birmingham B15 2TT, UK 2Department of Clinical Pharmacology, University of Oxford Oxford, OX2 6HE, UK 3Department of Pharmaceutical Sciences, Wayne State University Detroit, MI 48202, USA 4Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School Boston, MA 02129, USA 5Department of Engineering Science, University of Oxford Oxford, OX1 3PJ, UK

*To whom correspondence should be addressed. Tel: +44 121 627 2331; Fax: +44 121 472 0499; Email: mread{at}globalnet.co.uk

Received December 17, 2004. Revised February 10, 2005. Accepted May 9, 2005.

Synthetic vectors based on reducible polycations consisting of histidine and polylysine residues (HIS RPCs) were evaluated for their ability to deliver nucleic acids. Initial experiments showed that RPC-based vectors with at least 70% histidine content mediated efficient levels of gene transfer without requirement for the endosomolytic agent chloroquine. Significant gene transfer was observed in a range of cell types achieving up to a 5-fold increase in the percentage of transfected cells compared to 25 kDa PEI, a gold standard synthetic vector. In contrast to 25 kDa PEI, HIS RPCs also mediated efficient transfer of other nucleic acids, including mRNA encoding green fluorescent protein in PC-3 cells and siRNA directed against the neurotrophin receptor p75NTR in post-mitotic cultures of rat dorsal root ganglion cell neurons. Experiments to elevate intracellular glutathione and linear profiling of cell images captured by multiphoton fluorescent microscopy highlighted that parameters such as the molecular weight and rate of cleavage of HIS RPCs were important factors in determining transfection activity. Altogether, these results demonstrate that HIS RPCs represent a novel and versatile type of vector that can be used for efficient cytoplasmic delivery of a broad range of nucleic acids. This should enable different or a combination of therapeutic strategies to be evaluated using a single type of polycation-based vector.


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