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Trojan Horse For B-Cell Lymphoma

Sugar Chemistry: Chemical synthesis yields agents that target cancer cells

by Stu Borman
June 21, 2010 | A version of this story appeared in Volume 88, Issue 25

Delivery Vehicle
B cells bind sialic acid-based ligands on doxorubicin-armed liposomes, which kill the cells.
B cells bind sialic acid-based ligands on doxorubicin-armed liposomes, which kill the cells.

By using chemical synthesis to add sugars to the surface of Trojan horse-like liposomes with a payload of anticancer agent, researchers have killed human B-cell lymphoma cells in blood and in live mice. This type of approach could lead to new therapeutics for B-cell lymphomas and other conditions.

B-cell lymphomas, cancers of immune-system B cells, are currently treated with doxorubicin and other chemotherapy agents or with monoclonal antibodies such as rituximab. These treatments have some moderate to severe side effects, and many patients still die from these cancers each year, so scientists continue to seek new medications.

Now, chemical glycobiologist James C. Paulson of Scripps Research Institute and coworkers have come up with a novel way to attack B-cell lymphomas (Blood 2010, 115, 4778). They synthesized a sialic acid-based glycan that serves as a ligand for CD22, a receptor found on the surface of B cells. They pinned a lipid tail onto the glycan via a polyethylene glycol linker. When they added the conjugate to liposomes, the glycans arrayed on the liposome surface. They then loaded the liposome cavity with the anticancer agent doxorubicin.

The glycan-studded liposomes act like Trojan horses when they encounter B cells. The B cells’ CD22 receptors recognize and bind multivalently to the glycans, and the B cells then absorb the liposomes by endocytosis. Once inside the B cells, the liposomes deliver their doxorubicin cargo, killing the cells.

When the researchers administered a high dose of the liposomes to mice with human lymphoma, five of eight cancerous mice survived, whereas all of the mice in a control group died. Afterward, no tumor cells could be detected in the bone marrow of any of the treated mice. The treatment also destroyed B cells in blood samples from human patients with three types of B-cell lymphoma.

“This is a great example of how chemical synthesis can allow you to achieve a level of specificity that wouldn’t be accessible with natural glycans,” comments Laura L. Kiessling of the University of Wisconsin, Madison, a specialist in protein-glycan interactions.

The approach currently kills CD22-bearing macrophages as well as B cells, so Paulson and coworkers hope to refine it to further improve its selectivity. “But that doesn’t detract from their having demonstrated that this kind of strategy can work,” Kiessling says.

“We are very interested in moving this technology forward to see if it would be applicable to treatment of humans and to investigate other applications for this kind of targeting,” Paulson says.



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