Delivery of paclitaxel across cellular barriers using a dendrimer-based nanocarrier

The aim of this study was to investigate the ability of a third-generation (G3) polyamidoamine (PAMAM) dendrimer-based carrier to enhance the permeability of paclitaxel (pac) and to overcome cellular barriers. G3 dendrimers were surface modified with lauryl chains (L) and conjugated with paclitaxel (pac) via a glutaric anhydride (glu) linker, followed by labeling with FITC. Biological evaluation of the dendrimer and conjugates was conducted using the human colon adenocarcinoma cell line (Caco-2) and primary cultured porcine brain endothelial cells (PBECs). LDH assay was used to evaluate the cytotoxicity of the dendrimer and conjugates. Cytotoxicity studies showed that the conjugation of lauryl chains and paclitaxel on G3 dendrimer significantly (p < 0.05) increased the cytotoxicity against both cell types. Permeability studies of dendrimer-drug conjugates demonstrated an increase in the apparent permeability coefficient (P-app) in both apical to basolateral A -> B and basolateral to apical B -> A directions across both cell monolayers compared to unmodified G3 and free drug. The B -> A P-app of paclitaxel was significantly (p < 0.05) higher than the A -> B P-app, indicating active function of P-gp efflux transporter system in both cell models. L6-G3-glu-pac conjugate had approximately 12-fold greater permeability across both cell monolayers than that of paclitaxel alone. (C) 2012 Elsevier B.V. All rights reserved.