In vitro mammalian cytotoxicological study of PAMAM dendrimers - Towards quantitative structure activity relationships

Dendritic polymer nanoparticles such as polyamidoamine dendrimers (PAMAM) show exciting potential for biomedical applications. While the potential commercial applications of such dendrimers have received considerable attention, little is known about their possible adverse effects on both humans and the environment. In this study, the in vitro cytotoxicocity of full generation PAMAM dendrimers to two mammalian cell lines was investigated. Generations G4, G5 and G6 were chosen. Metabolic, lysosomal and mitochondrial activities were evaluated after 24 h exposure. Long term toxicity was evaluated using the clonogenic assay. Particle size and zeta potential were measured in all media. In culture medium, the particle size was largely unchanged from that observed in phosphate buffer. The zeta potential changed significantly, however, from positive in deionized water to negative in culture medium. A linear correlation was found between the change in zeta potential of the dendrimers in media and their surface area measured in phosphate buffer. The interaction of the dendrimer nanoparticles with 5% FBS supplemented media was also studied using UV/visible spectroscopy. The data suggest significant interaction of nanoparticles with FBS and other media components which increased with dendrimer generation. The toxicity also correlated linearly with the zeta potential and notably the change in zeta potential in the media, further pointing towards indirect toxic mechanisms. A trend of generation dependent toxic response and interaction of the dendrimers with the cell culture media was observed which may lay the basis of structure activity relationships.