title: Branched polyesters based on poly[vinyl-3-(dialkylamino)alkylcarbamate-co-vinyl acetate-co-vinyl alcohol]-graft-poly(d,l-lactide-co-glycolide): effects of polymer structure on cytotoxicity.
abstract: Branched polyesters of the general structure poly[vinyl-3-(dialkylamino)alkylcarbamate-co-vinyl acetate-co-vinyl alcohol]-graft-poly(d,l-lactide-co-glycolide) have shown potential for nano- and micro-scale drug delivery systems. For further optimization of this polymer class their cytotoxicity needs to be characterized establishing structure-toxicity relationships. Effects of type and degree of amine substitution as well as molecular weight on cytotoxicity were evaluated in L929 mouse fibroblasts using a MTT assay whereas interactions with cell membranes were quantified by LDH release and caspase (3/7)-activation. Finally, direct cell-polymer contact assays were conducted. Ungrafted amine-modified polymer backbone yielded IC(50) values in the range of 0.05-10mg/ml. Generally higher toxicities were observed with an increasing degree of amine substitution. Amine substituents could be ranked as diethylaminopropylamine (DEAPA)<diethylaminoethylamine (DEAEA)<dimethylaminopropylamine (DMAPA) but the degree of amine substitution was more dominant than the type of amine function. Membrane interactions seem to cause necrotic cell reactions in a dose-dependent manner for highly charged amine-poly(vinyl alcohol) (PVA) backbones. To attenuate cytotoxic effects DEAPA-PVA backbones were grafted with biodegradable PLGA side chains at molecular ratios of 1:10 and 1:20. Cytotoxicity of extracts of these polymers was significantly lower compared to ungrafted polymers possibly caused by shielding of polycationic backbone with hydrophobic PLGA side chains. P(33)-20, a polymer containing a sufficiently high degree of amine substitution could serve as a lead candidate for further investigations. In conclusion, structure-toxicity relationships could be established and shielding the polycationic backbone using PLGA side chains seems to be a promising strategy meriting further investigations.
authors.affiliation: Department of Pharmaceutics and Biopharmacy, Faculty of Pharmacy, Philipps-University Marburg, D-35037 Marburg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Unger
authors.forename: M
authors.initials: M
authors.lastname: Wittmar
authors.forename: T
authors.initials: T
authors.lastname: Kissel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001672:Biocompatible Materials / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects*; D008422:Materials Testing; D051379:Mice; D011091:Polyesters / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001672:Biocompatible Materials; D004337:Drug Carriers; D011091:Polyesters