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Friday, August 29, 2008

Tiny Drug Transporters

Cell signals: Researchers performed two tests to measure the efficacy of anticancer drugs delivered using carbon nanotubes. They found few proliferating cells (pink, top) and a much higher percentage of cell death (pink, bottom) compared with tumors that received other treatments. The researchers attribute this to the nanotube’s ability to leak into a tumors from blood vessels.
Credit: Hongjie Dai

An ideal cancer treatment would deliver a high dose of drugs to tumor sites while minimizing side effects. Unfortunately, as anticancer drugs are quickly cleared from the bloodstream, large doses are usually needed to ensure that enough drugs reach the tumor. And since these drugs can be absorbed by normal cells, high doses cause unpleasant side effects. Now research from Stanford University has shown that carbon nanotubes loaded with anticancer drugs can target tumor cells while steering clear of healthy tissue.

"Carbon nanotubes are one-dimensional, which sets them apart from other drug-delivery systems," says Hongjie Dai, a chemistry professor at Stanford, who led the research. The nanotubes--on average 100 nanometers long and a few nanometers wide--pass easily through the leaky walls of tumor blood vessels but do not get into healthy blood vessels. So the researchers realized that drugs attached to the nanotubes could be carried inside tumors without harming normal tissue.

To make working nano-drug transporters, the researchers coated the nanotubes with a molecule called polyethylene glycol (PEG), which has three branches on one end, then attached molecules of the anticancer drug paclitaxel to each branch. Each of the 100-nanometer-long nanotubes carried about 150 drug molecules in total. "Think of a carbon nanotube as a boat," says Steve Lippard, a chemistry professor at MIT, who was not involved in the research. "The advantage of the branched PEG is that you can have multiple passengers at each seat." Dai adds that the branched PEG is stable in the bloodstream for a relatively long time, giving the nanotubes more time to find and treat a tumor before leaving the body.

The drug-delivery technique was tested in mice that had been injected with breast cancer cells. Once the tumors grew to a specific size, the researchers administered a dose of the drug-laden nanotubes every six days. They gave another group of mice similar doses of different forms of paclitaxel, including the clinical drug Taxol, and left some untreated. After 22 days, they found that the tumors treated by nanotube delivery were less than half the size of the tumors treated by the second most effective treatment, Taxol.

The tumors treated with nanotube-delivered paclitaxel had a higher percentage of cell death and a smaller percentage of proliferating cells. The researchers estimate that drug uptake within a tumor was 10 times higher for nanotube delivery than for Taxol. This uptake means that smaller doses could be used to achieve the same effects as other treatments, reducing side effects.

However, despite such a dramatic improvement, lingering concern over the potential toxicity of carbon nanotubes means that they may be a long way from clinical use as a drug-delivery mechanism.

Dai's research suggests that carbon nanotubes accumulate in the liver and spleen and are cleared from the body through feces within a few months without causing lasting damage to organs. But "unlike nanoparticles that have been used for some time, such as gold, the safety of carbon nanotubes is not yet clearly established," says Bruce Weisman, a chemistry professor at Rice University. He adds that safety concerns will probably delay the approval of carbon nanotubes for medical purposes.

"Carbon nanotubes offer an interesting alternative [for drug delivery], if the toxicity does prove to be negligible," adds Lippard.

Nonetheless, the Stanford group plans to further investigate how the size of nanotubes affects drug circulation in the blood, penetration into both tumor and healthy cells, and the overall efficiency of drug delivery. Since there are relatively few anticancer drug carriers approved for clinical use, "there is a lot of room to develop this new drug-delivery method," says Dai.