Exploiting the Lactose–GM3 Interaction for Drug Delivery

Protein–protein and protein–carbohydrate interactions as a means to target the cell surface for therapeutic applications have been extensively investigated. However, carbohydrate–carbohydrate interactions (CCIs) have largely been overlooked. Here, we investigate the concept of CCI‐mediated drug delivery. Lactose‐functionalized β‐cyclodextrin (L‐β‐CD) hosting doxorubicin (Dox) was evaluated for site‐specific delivery to cancer cells via interaction with GM₃, a cell‐surface carbohydrate. The host–guest complex was evaluated in B16 melanoma cells, which express exceptionally high levels of GM₃, and acute monocytic leukemia (THP‐1) and mouse fibroblast (NIH‐3T3) cells, which lack GM₃ on the cell surface. Doxorubicin (Dox) was delivered more efficiently into B16 cells compared with NIH‐3T3 and THP‐1 cells. In B16 cells pretreated with sialidase or sodium periodate, thus preventing CCI formation, drug uptake was significantly decreased. Taken together, the results of these studies strongly support CCI‐mediated uptake via the GM₃–lactose interaction as the mechanism of controlled drug delivery.