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

Martin Piest, C. Lin, Miguel Mateos timoneda, Martin C. Lok, Wim E. Hennink, Jan Feijen, Johannes F.J. Engbersen

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageUndefined
Pages (from-to)38-45
JournalJournal of controlled release
Volume130
Issue number1
DOIs
Publication statusPublished - 2008

Keywords

  • IR-69322
  • METIS-254504

Cite this

@article{4c3485bfd6e94cf3a1e016c2105da123,
title = "Novel poly(amido amine)s with bioreducible disulfide linkages in their diamino-units: structure effects and in vitro gene transfer properties",
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.",
keywords = "IR-69322, METIS-254504",
author = "Martin Piest and C. Lin and {Mateos timoneda}, Miguel and Lok, {Martin C.} and Hennink, {Wim E.} and Jan Feijen and Engbersen, {Johannes F.J.}",
year = "2008",
doi = "10.1016/j.jconrel.2008.05.023",
language = "Undefined",
volume = "130",
pages = "38--45",
journal = "Journal of controlled release",
issn = "0168-3659",
publisher = "Elsevier",
number = "1",

}

Novel poly(amido amine)s with bioreducible disulfide linkages in their diamino-units: structure effects and in vitro gene transfer properties. / Piest, Martin; Lin, C.; Mateos timoneda, Miguel; Lok, Martin C.; Hennink, Wim E.; Feijen, Jan; Engbersen, Johannes F.J.

In: Journal of controlled release, Vol. 130, No. 1, 2008, p. 38-45.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Novel poly(amido amine)s with bioreducible disulfide linkages in their diamino-units: structure effects and in vitro gene transfer properties

AU - Piest, Martin

AU - Lin, C.

AU - Mateos timoneda, Miguel

AU - Lok, Martin C.

AU - Hennink, Wim E.

AU - Feijen, Jan

AU - Engbersen, Johannes F.J.

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

KW - IR-69322

KW - METIS-254504

U2 - 10.1016/j.jconrel.2008.05.023

DO - 10.1016/j.jconrel.2008.05.023

M3 - Article

VL - 130

SP - 38

EP - 45

JO - Journal of controlled release

JF - Journal of controlled release

SN - 0168-3659

IS - 1

ER -