Effects of polyether-modified poly(acrylic acid) microgels on doxorubicin transport in human intestinal epithelial Caco-2 cell layers

Novel microgels composed of cross-linked copolymers of poly(acrylic acid) and Pluronics were evaluated as possible permeation enhancers for doxorubicin transport using Caco-2 cell monolayers as a gastrointestinal model. Pluronic, triblock copolymers of ethylene oxide (EO) and propylene oxide (PO), were chosen to represent the most hydrophobic (Pluronic L61 and L92 with average compositions of EO₃PO₃₀EO₃ and EO₈PO₅₂EO₈, respectively) and the relatively hydrophilic (Pluronic F127 with average formula EO₉₉PO₆₇EO₉₉) extremes of this class of block copolymers. The weight ratio of Pluronic to poly(acrylic acid) in the microgels was set at 45:55. By inhibiting the P-glycoprotein (P-gp)-mediated doxorubicin efflux from the cells and enhancing the passive influx, the microgels were shown to enhance the overall cell absorption of doxorubicin. The enhancement effect was more pronounced than with a known penetration enhancer, Pluronic L61, and was comparable to that of Pluronic L92. Microgels exhibited synergism of the doxorubicin transport enhancement with Verapamil, a known inhibitor of the P-gp. The effects of the microgels were studied using the hydrophilic marker ([¹⁴C]mannitol) test and the MTT assay. Transepithelial electrical resistance (TEER) studies demonstrated that the microgels decreased TEER to about 80% of initial values, but these minor effects were fully reversible, indicating viability of the cells 14 after incubation with microgels. No significant enhancement of [14C]mannitol transport by microgels was observed, relative to Carbopol 934NF (control polymer). Cytotoxicity studies confirmed that the transport-enhancing properties of the microgels were not due to damage of the Caco-2 cell monolayers.