Monday, March 13, 2006

Designing Better Cancer Drugs

Insight into how carrier molecules move through tumors could lead to safer cancer treatments.

By Katherine Bourzac

Chemotherapy drugs wash in and out of tumors quickly and end up attacking healthy tissues. Increasing a drug's heft by attaching a larger molecule, called a drug carrier, could help chemotherapy drugs to penetrate deeply into tumors -- and stay there. But how to design these drug complexes to optimize their movement through the tumors is tricky business.

Researchers at Duke University, led by Ashutosh Chilkoti, associate professor of biomedical engineering, have now generated a wealth of information about how drug carriers move through tumors and what sizes are best for targeting the tumors. The group has worked with a polymer called dextran, but the results could apply to any polymer drug carrier. Chilkoti describes their research as "an engineering test to figure out approximate design rules for how you might want to design or select polymers for cancer drug delivery."

For 20 years, chemists have known, in theory at least, that they could take advantage of tumors' leaky blood vessels and nonexistent drainage systems -- if they could design and synthesize a drug carrier with the right molecular weight. Such bulked-up drugs would readily leak into tumor blood vessels, allowing the drug to accumulate where it is most needed.

Several polymer drug carriers are in clinical trials in the United States and one is already used in Japan. But the optimal design of these carrier molecules has been under debate. Indeed, their behavior in tumors has never been fully quantified before, according to Pavla Kopeckova, a research professor of pharmaceutics and pharmaceutical chemistry at the University of Utah.

Chilkoti and Matt Dreher, a Duke graduate student in biomedical engineering, studied the drug carrier in mice with human carcinoma tumors growing on their backs. The Duke researchers anesthetized mice, put them on a microscope platform, and injected fluorescently labeled drug carriers into their tail blood vessels. Through a Plexiglas window chamber sewn onto the mice's backs, "You can actually image the fluorescence as it starts to build inside the tumor, and you can track it for close to an hour," Chilkoti says.

Previous studies of the movement of polymer drug carriers through tumors relied on single image points, rather than a continuous stream of images like the ones Chilkoti's group acquired. Although they did not monitor healthy tissues, previous research suggests that such large molecules cannot easily pass through normal blood vessels.