Design and evaluation of folate-appended methyl-β-cyclodextrin as a new antitumor agent

Methyl-beta-cyclodextrin (M-beta-CyD) is widely used as a raft disrupting agent through extraction of cholesterol from lipid rafts which are highly expressed in cell membranes of tumor cells, but it does not have tumor cell-selective action. Meanwhile, the widespread use of folic acid (FA) as a tumor-targeting ligand has been known, because folate receptor (FR) overexpresses in various kinds of epithelial tumor cells. In the present study, in order to obtain more tumor cell-selectivity and antitumor activity of M-beta-CyD, we designed folate-appended M-beta-CyD (FA-M-beta-CyD), and evaluated its physicochemical properties and antitumor activity. The H-1-NMR study demonstrated that FA-M-beta-CyD having average degree of substitution of FA (DSF) of 1.0 was prepared. In addition, FA-M-beta-CyD (DSF 1.0) was found to be amorphous in a solid state and surface-active. Importantly, FA-M-beta-CyD (DSF 1.0) had potent cytotoxicity, compared to M-beta-CyD in KB cells, but not in A549 cells. These results suggest that FA-M-beta-CyD (DSF 1.0) has the potential as a novel antitumor agent.