Correlation between epithelial toxicity and surfactant structure as derived from the effects of polyethyleneoxide surfactants on caco-2 cell monolayers and pig nasal mucosa

The cell toxic effects of nonionic surfactants were investigated by means of two in vitro models, namely pig nasal mucosa mounted in horizontal Ussing chambers, and Caco-2 cell monolayers. A series of homologous polyethyleneoxide (PEO) surfactants with a wide span in hydrophilic head-group size and hydrophobic chain lengths were screened for concentration-dependent effects on the transepithelial electrical resistance (TEER) and mannitol permeability across Caco-2 cell monolayers. Trends in effects on permeability in the presence of increasing surfactant concentration coincided with the effects seen on TEER. Correlation of surfactant molecular structure with cell toxicity showed the size of the PEO group to be a more critical parameter than the size of the hydrocarbon chain. More specifically, the presence of very long PEO groups (>30 EO units) were found to lead to a decrease in cell toxicity. Similar trends were observed in the studies of the effects of PEO surfactants on pig nasal mucosa mounted in horizontal Ussing chambers. However, the nasal mucosa was somewhat more tolerant towards high surfactant concentrations than the Caco-2 cells. The relation between surfactant molecular structure and cell toxic effects is discussed in terms of micellar surface adsorption and micellar solubilization. The effect of the surfactants on the solubility of budesonide was investigated at two different surfactant concentrations (0.01 and 1 mg/mL). At the lower concentration, the solubilizing capacity of all of the surfactants was marginal, and there was no correlation between solubilizing capacity and cmc. At the higher concentration, on the other hand, all surfactants substantially increased the solubility of budesonide. The C18 PEO-ester with 40 EO units in the head group was found to be an efficient micellar solubilizer for budesonide, without causing adverse effects on the Caco-2 cell monolayers.