title: [Development of Cyclodextrin-based Cancer Treatment].
abstract: Drug delivery techniques to tumor cells have attracted considerable attention. For instance, folic acid (FA) as a tumor-targeting ligand is widely used because of overexpression of folate receptor-α (FR-α) in various kinds of epithelial tumor cells. On the other hand, methyl-β-cyclodextrin (M-β-CyD) is acknowledged to induce cell death through the extraction of cholesterol from lipid rafts. It was recently reported that intraperitoneal administration of M-β-CyD exerted antitumor activity in human tumor xenografted athymic nude mice. However, the cytotoxic activity of M-β-CyD is known to lack tumor cell selectivity. Therefore in the present study, in an attempt to confer tumor cell selectivity to M-β-CyD, we newly synthesized folate-appended M-β-CyD (FA-M-β-CyD) and evaluated its potential as a novel antitumor agent. FA-M-β-CyD showed potent antitumor activity in various FR-α-positive cells such as KB cells, Ihara cells, and M213 cells but not in FR-α-negative cells, A549 cells. FA-M-β-CyD induced the formation of autophagic vacuoles in KB cells. In addition, the antitumor activity of FA-M-β-CyD, but not M-β-CyD, was inhibited by addition of the autophagy inhibitors chloroquine and bafilomycin A1 in KB cells. A single intravenous injection of FA-M-β-CyD drastically inhibited tumor growth and significantly improved survival rate in Colon-26 cells-allografted or M213 cells-xenografted mice. In conclusion, FA-M-β-CyD has potential as a novel tumor-selective anticancer agent due to FR-α-mediated cellular uptake. The present results provide useful information for the design and development of novel antitumor drug carriers and antitumor drugs based on CyDs.
authors.affiliation: Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Motoyama
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D001343:Autophagy; D000077542:Eptifibatide; D066246:ErbB Receptors / Q000032:analysis; D006801:Humans; D037241:Mannose-Binding Lectins / Q000494:pharmacology*; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy*; D010455:Peptides / Q000032:analysis
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D037241:Mannose-Binding Lectins; D010455:Peptides; D066246:ErbB Receptors; D000077542:Eptifibatide