Supramolecular Complex of Methyl-β-cyclodextrin with Adamantane-Grafted Hyaluronic Acid as a Novel Antitumor Agent.

Methyl-β-cyclodextrin (M-β-CyD) exhibits cytotoxic activity, and has the potentials as an antitumor agent. However, a tumor-selectivity of M-β-CyD is low, leading to low antitumor activity and the adverse effects. Meanwhile, hyaluronic acid (HA) is known as a promising tumor targeting ligand, because various cancer cells overexpress CD44, a HA-binding glycoprotein. In the present study, to develop a tumor-selective delivery system for M-β-CyD, we designed a supramolecular complex of M-β-CyD with adamantane-grafted HA (Ad-HA/M-β-CyD) and evaluated it as a tumor-selective antitumor agent. M-β-CyD formed a stable complex with Ad-HA (K>10 M). In addition, Ad-HA/M-β-CyD formed slightly a negative-charged nanoparticle with ca. 140 nm of a particle size, indicating the favorable physicochemical properties for antitumor agents. Ad-HA/M-β-CyD showed the superior cytotoxic activity via CD44-mediated endosomal pathways in HCT116 cells (CD44(+)), a human colon cancer cell line. In addition, cytotoxic activity of Ad-HA/M-β-CyD was induced by apoptosis. These results suggest that Ad-HA/M-β-CyD has the potentials as a tumor-selective supramolecular antitumor agent.