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

摘要

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 IC50 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. (c) 2006 Elsevier Ltd. All rights reserved.