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Updated 2:30 PM July 7, 2005
 

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  Research
Nanotechnology saddles Trojan horse
to battle cancer cells more effectively

U-M scientists have created the nanotechnology equivalent of a Trojan horse to smuggle a powerful chemotherapeutic drug inside tumor cells—increasing the drug's cancer-killing activity and reducing toxic side effects.
A computer model of a manmade dendrimer with attached molecules. U-M scientists are using this nanotechnology to deliver cancer-fighting drugs directly to affected cells. (Photo by Jolanta Kukowska-Latello)

Previous studies in cell cultures have suggested that attaching anticancer drugs to nanoparticles for targeted delivery to tumor cells could increase the therapeutic response. Now, scientists have shown that this nanotechnology-based treatment is effective in living animals.

"This is the first study to demonstrate a nanoparticle-targeted drug actually leaving the bloodstream, being concentrated in cancer cells, and having a biological effect on the animal's tumor," says Dr. James R. Baker Jr., the Ruth Dow Doan Professor of Biologic Nanotechnology, who directed the study.

"We're very optimistic that nanotechnology can markedly improve cancer therapy," says Baker, who directs the Michigan Nanotechnology Institute for Medicine and the Biological Sciences. "Targeting drugs directly to cancer cells reduces the amount that gets to normal cells, increases the drug's anti-cancer effect and reduces its toxicity. By improving the therapeutic index of cancer drugs, we hope to turn cancer into a chronic, manageable disease."

Results of the study were published in the June 15 issue of Cancer Research.

The drug delivery vehicle used by U-M scientists is a manmade polymer molecule called a dendrimer. Less than five nanometers in diameter, these dendrimers are small enough to slip through tiny openings in cell membranes. One nanometer equals one-billionth of a meter, which means it would take 100,000 nanometers lined up side-by-side to equal the diameter of a human hair.

Dendrimers have a tree-like structure with branches where scientists can attach a variety of molecules, including drugs.

"It's like a Trojan horse," Baker explains. "Folate molecules on the nanoparticle bind to receptors on tumor cell membranes and the cell immediately internalizes it, because it thinks it's getting the vitamin it needs. But while it's bringing folate across the cell membrane, the cell also draws in the methotrexate that will poison it."

In conventional chemotherapy, drugs like methotrexate must diffuse across a cell membrane to get inside cancer cells, according to Baker. It's a slow process and requires a high concentration of drug in the extra-cellular fluid, which can damage normal cells and tissues.

When tested in laboratory mice that had received injections of human epithelial cancer cells, the nanoparticle-based therapy using folic acid and methotrexate was 10 times more effective at delaying tumor growth than the drug given alone. Nanoparticle treatment also proved to be far less toxic to mice in the study than the anticancer drug alone.

"In our longest trial, which lasted 99 days, 30 percent to 40 percent of the mice given the nanoparticle with methotrexate survived," says Jolanta Kukowska-Latallo, a U-M research investigator and first author of the study. "All the mice receiving free methotrexate died—either from overgrowth of the tumor or from toxic effects of the drug.

"We saw statistically significant tumor growth reduction in all the mice given targeted nanoparticle therapy, as opposed to mice receiving either free methotrexate or the dendrimer alone," Kukowska-Latallo adds. "Effectively, we achieved a 30-day tumor growth delay. Taking into account the length of a mouse's life, that is significant. One month for a mouse is about three years for a person."

Researchers at the institute are planning to explore the use of nanotechnology-based therapies using other chemotherapeutic drugs. By attaching different targeting molecules and different drugs to the nanoparticle, Baker believes scientists eventually will be able to develop effective therapies for many types of cancer, perhaps even personalized therapy for an individual's specific cancer.

Other U-M participants in the research study are Zhengyi Cao and Shraddha S. Nigavekar, research associates; Istvan J. Majoros, research investigator; and Thommey P. Thomas, assistant research professor.

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