Poly(amido amine) copolymers derived from aminobutanol and ethylene diamine are excellent carriers for siRNA delivery

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Aa van der, L.J. and Vader, P. and Schiffelers, R.M. and Engbersen, J.F.J. (2010) Poly(amido amine) copolymers derived from aminobutanol and ethylene diamine are excellent carriers for siRNA delivery. Journal of Controlled Release, 148 (1). e85-e86. ISSN 0168-3659

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Abstract:The variation of the alkyl chain length in ω-hydroxyalkyl side chains in disulfide based poly(amido amine)s (SS-PAA) was investigated to optimize an existing butanol-containing polymer for gene silencing. The chain length does not significantly affect particle formation and gene knockdown, but has influence on the cytotoxicity and hemolysis of the polyplexes. The existing butanol-containing polymer appeared to be the best candidate, since it shows excellent gene silencing properties and negligible cytotoxicity.

Introduction

Gene therapy has developed itself in the past decades to a promising strategy to cure an innumerable range of diseases. The discovery of RNAi even elevated this field to a higher level, since its mediator, short interfering RNA (siRNA), does not have to enter the nuclear envelop to be effective. Although gene therapy has still a high potential, the efficient and safe delivery of the nucleotides to the target side is still a bottleneck in the clinical application. Polymeric carriers appear to be a good candidate to fulfill this gap.

In our recent research we have found that disulfide based poly(amido amine) (SS-PAA) copolymers can act as highly efficient carriers for siRNA delivery [1]. These SS-PAA copolymers contain disulfides in the main chain for a rapid intracellular degradation, diaminoethyl units in the main chain for optimal complexation of the short nucleotides, and butanol side chains for hydrophobic membrane interactions. Previous work of our group on plasmid delivery showed that SS-PAA homopolymers with pentanol side chains gave higher gene expression than those with butanol side chains [2], but due to a lower solubility, the pentanol derivatives are more difficult to handle than the butanol analogs. Anderson et al. also showed a higher gene expression for similar poly (β-amino ester)s [3]. However, solubility problems play a minor role in polymers containing diaminoethyl units, since the (protonated) extra amine groups do not only provide extra nucleotide interaction, but also better water solubility. This enabled us to study the effects of variation of the length of the alcoholic side group in the SS-PAA copolymers on the gene vector properties. In this study we prepared five SS-PAAs differing in alcohol side chain length (Fig. 1) and studied their effect on polyplex formation, knockdown, cytotoxicity and hemolysis.

Item Type:Article
Copyright:© 2010, Elsevier
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Science and Technology (TNW)
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Link to this item:http://purl.utwente.nl/publications/77533
Official URL:http://dx.doi.org/10.1016/j.jconrel.2010.07.061
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