Assessing toxicity of polyamidoamine dendrimers by neuronal signaling functions

We report for the first time on neuronal signaling for the evaluation of interactions between native plasmamembrane and polyamidoamine (PAMAM) dendrimers. Generation 5 polycationic (G5-NH2), novel β-D-glucopyranose- conjugated G5-NH2 and generation 4.5 polyanionic (G4.5-COONa) polyamidoamine (PAMAM) dendrimers (1-0.0001 mg/ml) were applied in acute brain slices. Functional toxicity assessments-validated by fluorescence imaging of dead cells-were performed by employing electrophysiological indicators of plasma membrane breakdown and synaptic transmission relapse. Irreversible membrane depolarization and decrease of membrane resistance predicted substantial functional neurotoxicity of unmodified G5-NH2, but not of the G4.5-COONa PAMAM dendrimers. Model calculations suggested that freely moving protonated NH2 groups of terminal monomeric units of PAMAM dendrimers may be able directly destroy the membrane or inhibit important K⁺ channel function via contacting the positively charged NH2. In accordance, conjugation of surface amino groups by β-D-glucopyranose units reduced functional neurotoxicity that may hold great potential for biomedical applications.