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

• Published in: Biomaterials Vol. 28; no. 9; pp. 1610 - 1619
• Main Authors: Unger, F, Wittmar, M, Kissel, T
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01-03-2007
• Subjects: Advanced Basic Science; Animals; Apoptosis - drug effects; Biocompatible Materials - chemistry; Biocompatible Materials - pharmacology; Cell Line; Cell Survival - drug effects; Copolymer; Cytotoxicity; Degradation; Dentistry; Drug Carriers - chemistry; Drug Carriers - pharmacology; Fibroblasts - cytology; Fibroblasts - drug effects; Materials Testing; Mice; Poly(vinyl alcohol); Polyesters - chemistry; Polyesters - pharmacology; Polyglycolic acid; Polylactic acid; Structure-Activity Relationship; Polyglycolic acid; Degradation; Cytotoxicity; Poly(vinyl alcohol); Copolymer; Polylactic acid
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2006.12.002

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 IC50 values in the range of 0.05–10 mg/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.