title: An acetal-based PEGylation reagent for pH-sensitive shielding of DNA polyplexes.
abstract: p-Piperazinobenzaldehyde methoxy poly(ethylene glycol) (mPEG, 5 kDa) acetal was synthesized by the Buchwald-Hartwig coupling reaction from piperazine and p-bromobenzaldehyde mPEG acetal. Introduction of a maleimide moiety yielded a novel acetal-based PEGylation reagent (PEG-acetal-MAL) for pH-sensitive conjugation of PEG to thiol-functionalized biomolecules. For reversible shielding of polyplexes, PEG-acetal-MAL was conjugated to polyethylenimine (PEI). At 37 degrees C, the PEG-acetal-PEI conjugate had a half-life of 3 min at endosomal pH 5.5 and 2 h at physiological pH 7.4, respectively. PEI polyplexes containing PEG-acetal-PEI had a zeta potential of +3 mV and were stable to salt-induced aggregation for 2 h at pH 7.4. In contrast, at endosomal pH, the particles were deshielded and aggregated within 0.5 h. Epidermal growth factor or transferrin receptor-targeted polyplexes shielded with the pH-sensitive PEG-acetal mediated enhanced luciferase gene expression in receptor-expressing target cells (Renca-EGFR or K562) as compared to stably shielded control polyplexes. Thus, the novel PEG-acetal-MAL reagent may present a versatile tool for drug and gene delivery formulations when pH-sensitive PEGylation is preferred.
authors.affiliation: Pharmaceutical Biology-Biotechnology, Department of Pharmacy Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, D-81377 Munich, Germany.
authors.forename: Veronika
authors.initials: V
authors.lastname: Knorr
authors.forename: Lars
authors.initials: L
authors.lastname: Allmendinger
authors.forename: Greg F
authors.initials: GF
authors.lastname: Walker
authors.forename: Franz F
authors.initials: FF
authors.lastname: Paintner
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
mesh_terms: D000080:Acetals / Q000737:chemistry*; D000818:Animals; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry*; D016503:Drug Delivery Systems; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007202:Indicators and Reagents / Q000737:chemistry; D020014:K562 Cells; D008156:Luciferases / Q000235:genetics; D008301:Maleimides / Q000737:chemistry*; D051379:Mice; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry*; D011094:Polyethyleneimine / Q000737:chemistry*; D014162:Transfection
chemical_list: D000080:Acetals; D007202:Indicators and Reagents; D008301:Maleimides; C043592:maleimide; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D004247:DNA; D008156:Luciferases