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.
authors.affiliation: Department of Biomedical Chemistry, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: Piest
authors.forename: Chao
authors.initials: C
authors.lastname: Lin
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Mateos-Timoneda
authors.forename: Martin C
authors.initials: MC
authors.lastname: Lok
authors.forename: Wim E
authors.initials: WE
authors.lastname: Hennink
authors.forename: Jan
authors.initials: J
authors.lastname: Feijen
authors.forename: Johan F J
authors.initials: JF
authors.lastname: Engbersen
mesh_terms: 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
chemical_list: D001672:Biocompatible Materials; D003959:Diamines; D004220:Disulfides; D011073:Polyamines; D004247:DNA