Evaluation of the cytotoxicity of beta-cyclodextrin derivatives: evidence for the role of cholesterol extraction.

Several beta-cyclodextrin (beta-CD) derivatives have been synthesized recently to improve the physicochemical properties and inclusion capacities of the parent molecule, however, there is limited information available about their cytotoxic effects. In this study we investigated the cytotoxic and hemolytic properties of various beta-CDs in correlation with their cholesterol-solubilizing capacities to expose the mechanism of toxicity. MTT cell viability test, performed on Caco-2 cells showed significant differences between the cytotoxicity of beta-CD derivatives. Cell toxicity of methylated-beta-CDs was the highest, while ionic derivatives proved to be less toxic than methylated ones. Most of the second generation beta-CD derivatives, having both ionic and methyl substituents showed less cytotoxicity than the parent compounds both on Caco-2 cells and human erythrocytes. Inclusion of cholesterol into the ring of randomly methylated-beta-CD and heptakis(2,6-di-O-methyl)-beta-CD abolished the cell toxicity indicating the role of cholesterol extraction in cytotoxicity. These data demonstrate the correlation between the cytotoxic effect, hemolytic activity and the cholesterol complexation attributes of beta-CD derivatives and we propose that cholesterol-solubilizing properties can be a predictive factor for beta-CD cell toxicity.