Self-Assembling Carbohydrates Trap Cancer Cells In A Cage

Chemists have designed a carbohydrate-based molecule that can surround and strangle bone cancer cells by self-assembling into a tangled web of nanofibers (J. Am. Chem. Soc. 2014, DOI: 10.1021/ ja5111893). The molecule spares healthy cells because its assembly is triggered by an enzyme that’s overexpressed on cancer cells.

The inspiration for spinning a molecular cage around cells came from nature, says Rein V. Ulijn of the City University of New York’s Hunter College. Many of the body’s cells are enmeshed in an extracellular matrix—a complex web of biomolecules that provides structure for tissues, facilitates intercellular communication, and traps nutrients. Scientists are developing molecules that spontaneously assemble into simpler versions of this matrix to provide a growth medium for cells, in particular for tissue engineering.

The field has focused mainly on self-assembling peptides. In a recent study, Bing Xu of Brandeis University and colleagues designed a nonnurturing peptide that aggregates and engulfs cancer cells only when its phosphate group is removed (Angew. Chem. Int. Ed. 2014, DOI: 10.1002/anie.201402216). The phosphate-free peptides have a hydrophilic end and a hydrophobic one, which allow them to assemble like lipids in a cell membrane. The negative charge on the phosphate groups creates electrostatic repulsion between the molecules and prevents this. This phosphate on-off switch is great for targeting cancer because some types of cancer cells overexpress alkaline phosphatase, an enzyme that cleaves phosphates.

Ulijn and his colleagues, including Iva Pashkuleva of the University of Minho, in Portugal, thought they could get carbohydrate-based molecules to behave the same way. Compared with peptides, Ulijn says, carbohydrates can lead to more diverse structures, opening up new possible applications. So to make their web-weaving molecules, the researchers first took the hydrophilic carbohydrate glucosamine and added a hydrophobic aromatic group to create a molecule that would self-assemble. They then added a phosphate group to the sugar.

To test the molecule’s cancer-killing prowess, the researchers added it to cultures of bone cancer cells as well as to normal cartilage cells, which have only about 5% of the alkaline phosphatase activity observed in the cancerous ones. After seven hours, about 95% of the bone cancer cells had died, while only 15% of the cartilage ones were dead.

Scanning electron microscope images of the cells revealed a cagelike hydrogel on the surface of the bone cancer cells. Although the mechanism of cell death remains unknown, Ulijn suspects the nanofiber cage suffocates the cancer cells, neither allowing nutrients in nor waste products out.

The study nicely demonstrates that high enzyme activity can serve as a way to target cancer cells, Brandeis’s Xu says. One concern Xu has is that the team needed to use concentrations of the molecule that are higher than are typical for drugs. High concentrations often require large doses for patients, which usually mean high risk of side effects. Ulijn agrees that his team needs to study possible side effects of their self-assembling carbohydrates.