Influence of Surface Chemistry of Poly(Amidoamine) Dendrimers on

ABSTRACT: The objective of this research was to investigate the effect of surface charge of poly(amidoamine), PAMAM, dendrimers on the integrity, paracellular permeability, and viability of Caco-2 cell monolayers by monitoring the transepithelial electrical resistance (TEER), mannitol permeability, and leakage of lactate dehydrogenase (LDH) enzyme, respectively. Neutral PAMAM– OH, generations 2–4 (G2–G4), and anionic PAMAM–COOH (G-0.5–G4.5) dendrimers were incubated with Caco-2 cell monolayers at donor concentrations of 0.1, 1.0, and 10.0mM for 90, 150, and 210min. Neutral G2–G4 and anionic G-0.5, G0.5, G1.5 and G4.5 dendrimers did not cause any significant change in TEER or mannitol permeability across Caco-2 cell monolayers. Anionic G2.5 and G3.5 dendrimers, however, caused an incubation time-dependant decline in TEER values and up to a 6-fold increase in mannitol permeability. All anionic PAMAM–COOH dendrimers caused an incubation time-, concentration-, and generation-dependant LDH leakage that was not observed with neutral PAMAM–OH dendrimers. These studies suggest a size and/or charge ‘‘window’’ where anionic dendrimers may enhance paracellular transport across Caco-2 cell monolayers further confirming their potential as drug carriers and permeation enhancers for oral drug delivery. *Author to whom correspondence should be addressed