Thursday, September 18, 2008
Researchers find a new way to precisely target cancer drugs.
| Tiny target: A new targeted nano carrier selectively brings a cancer-killing drug to the mitochondria, the drug’s subcellular site of action. In these fluorescent images, yellow indicates that the drug is inside the mitochondria. Cell nuclei are stained blue.
Credit: Volkmar Weissig
Most drugs work by affecting a particular organelle within cells, but it's difficult to get a therapeutic compound to the right place inside a cell. Now researchers have succeeded in targeting a cancer-killing drug to a part of the cell called the mitochondrion by packaging it in a nano carrier. The highly targeted version of the drug increased its efficacy in tests in mice, even at relatively low doses, shrinking tumors and extending survival.
Over the past several years, researchers have had great success using antibodies and other molecules to target drugs to cells of particular tissue types. But once a drug gets inside the right cell, it's easy for it to get lost. Drugs are tiny compared with cells, and their charge, weight, and tendency to interact with water all determine where in the cell a drug ends up. "You have to design it such that it finds its way," says Volkmar Weissig, a professor of pharmacology at the Midwestern University College of Pharmacy, in Glendale, AZ, who developed the new targeted therapy with Vladimir Torchillin, director of the Center for Pharmaceutical Biotechnology and Nanomedicine, at Northeastern University, in Boston.
Subcellular targeting "is one of the biggest promises nanotechnology offers," says Jerry Lee, a project manager at the National Cancer Institute's Alliance for Nanotechnology in Cancer. The new research, he says, "offers early proof of concept of being able to target not only to cancer cells, but to pick and choose where in the cell to target."
Weissig and Torchillin developed a nano carrier to deliver a drug called ceramide to the mitochondria of cancer cells. The researchers enclosed ceramide within a sphere of lipids similar to those in many drug-delivery systems. This lipid envelope, which is too large to pass through the walls of healthy blood vessels, has a tendency to passively accumulate in tumors. (Tumor blood vessels have large gaps that allow the lipid-coated drugs in.) In order to actively target the drug to its subcellular site of activity, Weissig and Torchillin decorated the lipid envelopes with a molecule known to accumulate in the mitochondria.
In animal tests, the approach shows good efficacy, says Joseph DeSimone, a professor of chemistry and chemical engineering at the University of North Carolina at Chapel Hill. DeSimone is taking a different approach to intracellular targeting: he recently found that it's possible to control where in the cell nanoparticles accumulate by varying their shape. Overall, he says, "methods for accessing intracellular targets are extremely important to pursue."
Unhealthy mitochondria play a role in obesity and many diseases, including diabetes and degenerative diseases of the nervous system and muscle. And in theory, the nano-carrier system could be used to carry a wide variety of drugs to the mitochondria, says Weissig. However, since the carrier relies on leaky blood vessels to get to its target cells, it's not likely to be used to treat a wide variety of other diseases. Inflammatory diseases like arthritis, which also causes leaky blood vessels, are another possible application.
The nano-carrier technology was recently licensed by Telomolecular, a company in Rancho Cordoba, CA. Weissig says that the company will use it to develop an anticancer drug that works in the mitochondria. Although the system was proved using ceramide, Telomolecular will test other cancer drugs as well, says Weissig.