Designing Better Cancer Drugs
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.
Utah’s Kopeckova says there has been heated discussion for a decade “about the size of the carrier of the drug, and I think this paper will bring lots of details which were missing.” She’ll use the new information in her work on a carrier for an ovarian cancer drug that finds tumors by recognizing markers on their cells.
Chilkoti has already begun applying the results to his work on a synthetic protein drug carrier that becomes insoluble in the blood at 42 degrees Celsius (five degrees above normal body temperature). Technologies have already been developed to heat tumors from the outside, using ultrasound and microwaves, and Chilkoti’s drug carrier would piggyback on these techniques. “The idea is when you turn on the heat, these things become insoluble, they form particles inside the tumor. So it’s like implanting little tablets of drug,” he says. “Then when you turn the heat off, they dissolve from this very high concentration and penetrate throughout the tumor.” Chilkoti says this therapy would work well with breast cancer.
But Chilkoti also stresses that his group’s study of the detailed mechanisms of drug carriers is only a starting point. “You would use this information to design and select your carrier, and then you would want to go into clinical trials and see if it works,” he says.
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