Novel poly(amido amine)s with bioreducible disulfide linkages in their diamino-units: Structure effects and in vitro gene transfer properties

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Piest, Martin and Lin, Chao and Mateos Timoneda, Miguel A. and Lok, Martin C. and Hennink, Wim E. and Feijen, Jan and Engbersen, Johan F.J. (2008) Novel poly(amido amine)s with bioreducible disulfide linkages in their diamino-units: Structure effects and in vitro gene transfer properties. Journal of Controlled Release, 130 (1). pp. 38-45. ISSN 0168-3659

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Abstract:A series of novel water-soluble, bioreducible poly(amido amine)s containing disulfide linkages in their amino units (SS-PAAs) was synthesized by Michael addition polymerization of N,N′-dimethylcystamine (DMC) with various bisacrylamides. The synthetic route allows large structural variation in the bisacrylamide segments and is complementary to the earlier developed route to SS-PAAs in which the disulfide bond is incorporated in cystamine bisacrylamide units. The physicochemical and biomedical properties of the novel DMC-based polymers were evaluated for their application as non-viral gene delivery vectors and compared with analogs lacking the disulfide moieties. DMC-based SS-PAAs show high buffer capacities in the pH range pH 5.1–7.4, a property that may favorably contribute to the endosomal escape of the polyplexes. The polymers are capable to condense DNA into nanoscaled (< 250 nm) and positively charged (>+ 20 mV) polyplexes which are relatively stable in medium mimicking physiological conditions but rapidly disintegrate in the presence of 2.5 mM DTT, mimicking the intracellular reductive environment. Polyplexes from DMC-based SS-PAAs are capable to transfect COS-7 cells in vitro with transfection efficiencies up to 4 times higher than those of pDMAEMA and PEI, with no or only very low cytotoxicity at the polymer/DNA ratios where the highest transfection is observed. The results show that DMC-based SS-PAAs have very promising properties for the development of potent and non-toxic polymeric gene carriers.
Item Type:Article
Copyright:Elsevier B.V.
Faculty:
Science and Technology (TNW)
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Link to this item:http://purl.utwente.nl/publications/69322
Official URL:http://dx.doi.org/10.1016/j.jconrel.2008.05.023
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