Mannose-methyl-β-cyclodextrin suppresses tumor growth by targeting both colon cancer cells and tumor-associated macrophages

Methylated beta-cyclodextrin (M beta CD) can extract cholesterol from lipid rafts and induce apoptosis in cancer cells by inhibiting activation of the PI3K-Akt-Bad pathway. In this study, we modified M beta CD with mannose (Man-M beta CD) and assessed its in vitro and in vivo potential for targeting colon cancer cells expressing the mannose receptor (MR) and tumor-associated macrophages (TAM). Man-M beta CD showed a significantly greater level of cellular association with colon-26 cells and M2 macrophages, and much more prominent anticancer activity than that of M beta CD against MR-positive colon-26 cells. These results revealed that autophagy was the main mechanism of cell death associated with Man-M beta CD. Furthermore, compared with M beta CD, Man-M beta CD significantly reduced tumor development following intravenous delivery to tumor-bearing mice, with no apparent side effects. Thus, Man-M beta CD has the potential to be a novel anticancer drug.