SN38 is a powerful anticancer drug for metastatic colorectal cancer (CRC). The main challenge is selectively exposing cancer cells to avoid toxicity and side effects. Based on observations that some cancer cell lines actively take up a specific type of sugar called fucose, its potential use in drug targeting was investigated. In this study, fucose-bound nanoparticles were used to deliver SN38 specifically to cancer cells.
In the body, fucose is often involved in different recognition systems such as blood group determination, immunological reactions and signal transduction pathways. Although the precise mechanisms are unclear, increased levels of fucose were found in the serum and urine of cancer patients, suggesting an increased use of this sugar in cancer cells. Certain cultured cell lines have indeed been shown to actively incorporate fucose and in turn secrete fucose-labelled proteins. Initial results have indicated that its accumulation is associated with the acceleration of the malignant potential of colorectal cancers.
The nuts and bolts
Investigation of tumor tissues from 50 CRC patients who underwent resection revealed that more advanced CRC correlates with a higher accumulation of fucose. The results suggest that fucosylated proteins might be required for disease progression and play an important role in inducing metastatic potential.
As their need for fucose would be higher, it was investigated whether these cells could be targeted by fucose-bound liposomes, a kind of vesicles made from lipids. These vesicles contained a fluorescent dye and were added to cancer cell cultures. Using microscopy, it could be seen that the dye was taken up by the CRC cells. Adding an excess of fucose to the cells first, slowed the uptake, suggesting that the fucose bound to the vesicles is involved in the recognition and uptake by the cells.
To investigate whether this strategy could also be used to deliver cytotoxic drugs to the cells, fucosylated and non-fucosylated liposomes containing the compound SN38 were added separately to CRC cells. The fucosylated liposomes were able to kill CRC cells more efficiently than the control without fucose.
The growth of other cancer cell lines that also produce fucosylated proteins, such as pancreatic and biliary cancer, was also effectively suppressed by the fucose-labeled liposome containing anticancer drugs. No cytotoxicity in normal cells was found, probably because of their low requirement of fucose.
In mice, these fucose-labelled vesicles could also selectively deliver fluorescent dye to tumor cells. A three-week treatment with SN38 in fucose-labelled liposomes made the tumors disappear almost completely. No adverse effects, including body weight changes, were observed during this study.
How will this help me?
Being able to specifically and efficiently deliver cytotoxic drugs to CRC cells is of great importance. The next steps are the confirmation of the study’s results using a large number of CRC patients. The strategy could also be investigated as a generalized approach for the treatment of a wide variety of other fucosylated protein producing cancer types. When the results are confirmed, this promising strategy can then be translated to human patients and subjected to clinical trials.
Relationship Between Increased Fucosylation and Metastatic Potential in Colorectal Cancer – Journal of the National Cancer Institute (2016).