Novel poly(amido amine)s with bioreducible disulfide linkages in their diamino-units: structure effects and in vitro gene transfer properties.
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.
Piest
Martin
M
Department of Biomedical Chemistry, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands.
Lin
Chao
C
Mateos-Timoneda
Miguel A
MA
Lok
Martin C
MC
Hennink
Wim E
WE
Feijen
Jan
J
Engbersen
Johan F J
JF
D000818:Animals; D001672:Biocompatible Materials / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry*; D019556:COS Cells; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004247:DNA / Q000008:administration & dosage; D003959:Diamines / Q000737:chemistry; D004220:Disulfides / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods*; D018014:Gene Transfer Techniques; D008027:Light; D008970:Molecular Weight; D011073:Polyamines / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry*; D012542:Scattering, Radiation; D013329:Structure-Activity Relationship; D014162:Transfection
D001672:Biocompatible Materials; D003959:Diamines; D004220:Disulfides; D011073:Polyamines; D004247:DNA