title: Acetal linked oligoethylenimines for use as pH-sensitive gene carriers.
abstract: Two types of acid-degradable nonviral gene carriers, OEI-MK and OEI-BAA, were synthesized by polymerizing oligoethylenimine of 800 Da (OEI800) with the pH-sensitive acetone ketal cross-linker 2,2-bis(N-maleimidoethyloxy) propane (MK) or the 4-methoxybenzaldehyde bisacrylate acetal cross-linker 1,1-bis-(2-acryloyloxy ethoxy)-[4-methoxy-phenyl]methane) (BAA). Corresponding acid-insensitive counterparts (OEI-BM and LT-OEI-HD) were synthesized as well, representing control polymers. Kinetics of hydrolysis were measured and confirmed the pH-dependent degradation profile of the acetal functions, with short half-lives of 3 min at pH 5.0, and 5 h (OEI-MK) or 3.5 h (OEI-BAA) at physiological pH 7.4 and 37 degrees C. DNA polyplexes of a luciferase expression plasmid were tested for gene transfer efficiency and biocompatibility in two cell lines (B16F10 and Neuro2A). Polyplexes with acid-labile polymers showed an improved toxicity profile compared to those made with acid-stable polymer analogues. At low cation/plasmid (c/p) w/w ratios the transfection efficiency of pH-sensitive polymers was slightly reduced, but it became similar or superior to the efficiency of acid-stable polymers at higher c/p ratios. An improved in vivo biocompatibility of the acid-degradable polymers over the stable control polymers was confirmed by liver histology after systemic administration of polymers in Balb/c mice.
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: Verena
authors.initials: V
authors.lastname: Russ
authors.forename: Lars
authors.initials: L
authors.lastname: Allmendinger
authors.forename: Manfred
authors.initials: M
authors.lastname: Ogris
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
mesh_terms: D000080:Acetals / Q000737:chemistry*; D000818:Animals; D001388:Aziridines / Q000737:chemistry*; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism*; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D006838:Hydrocarbons / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010316:Particle Size; D011108:Polymers / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D012680:Sensitivity and Specificity; D014162:Transfection
chemical_list: D000080:Acetals; D001388:Aziridines; D004337:Drug Carriers; D006838:Hydrocarbons; D011108:Polymers; C033132:aziridine; D004247:DNA; D008156:Luciferases