Harnessing Fat to Attack Cancer
Scientists at Duke University Medical Center and Duke's Pratt School of Engineering have harnessed the much maligned fat particle to serve a higher purpose: battling human cancers. The researchers have engineered microscopic fat bubbles into "smart bombs" by packing them with anticancer drugs and dispatching them on a mission to seek and destroy cancerous tumors.
Heating the tumor from the outside with microwave energy attracts the anticancer bombs to the tumor, the scientists said.
Within 20 seconds of reaching the feverish tumor, the fat bubbles, or "liposomes," melt and dump their contents, producing a virtual flood of drug that is far more potent than the slow infusion of traditional chemotherapy, a new study in rats has shown.
The scientists have begun testing the new heat-sensitive liposome in women whose breast cancers have recurred in their chest wall.
"Encapsulating the drugs inside of fat liposomes and infusing them into the bloodstream enables us to deliver 30 times more chemotherapy than we normally could to the tumor site," said senior investigator Mark Dewhirst, D.V.M., Ph.D., professor of radiation oncology and director of the hyperthermia program. "The liposomes melt only within the tumor, and the rest of the body receives relatively less of the toxic drug."
The scientists report their results in the Jan. 2, 2007, issue of the Journal of the National Cancer Institute. The research was funded by the National Cancer Institute.
Dewhirst said his team is the first to demonstrate and report how these heat-sensitive liposomes disperse their contents in real time, using three-dimensional magnetic resonance images to display how the drug enters a tumor and sweeps across its terrain. The drug appears as a white veil that drapes the tumor, said Ana Ponce, a graduate student who works with Dewhirst and is first author of the journal report.
Most importantly, the findings demonstrate how to achieve the highest drug levels around the tumor's outer edges, which are rich in blood vessels that nourish the tumor, the scientists said. "Blanketing this area with drug destroys the tumor's source of sustenance," Dewhirst said. "We found that this results in the greatest shrinkage of tumors."
In the study, the researchers administered heat to rodents either before, during or after they received intravenous infusions of liposomes.
Rats that received the liposomes and heat in unison showed the best response to treatment, the study showed. Using this method, two of the seven rats showed complete shrinkage of their tumors. The other five rats showed a significant delay in tumor growth that extended their survival for 35 days longer than control rats that did not receive therapy, he said. For rats, 35 days is equal to several years in humans.
Rats that received the drug either before or after the tumor was heated did not demonstrate the same level of tumor shrinkage as rats that received the two therapies together, the scientists said. In these cases, drug levels achieved equally high concentrations, but localized to different portions of the tumor where it was less effective at inhibiting tumor growth.
In previous Duke studies in women with breast cancer, reported in 2003, researchers found that administering heat therapy in combination with drug-filled liposomes dramatically shrank their tumors, but these studies did not use heat-sensitive liposomes.
The new liposome, formulated by Duke engineer David Needham, Ph.D., has undergone initial testing in women with chest wall recurrences of breast cancer. During treatment, women receive an infusion of liposomes. Immediately afterward, microwave energy is directed toward the chest wall to heat the tumor. Heating takes place afterward because the drug is metabolized more slowly in humans than in rats. By the time the liposome reaches the tumor, it is already heated, Dewhirst said.
Dewhirst said the heat makes the tumor's blood vessels porous, and the liposomes easily slip out of the bloodstream and into the tumor.
"A tumor's blood vessels are much leakier than normal blood vessels," he said. "Heat pulls the blood vessels apart even more than usual, allowing tiny particles such as liposomes to leak out and pool inside the tumor."
As the liposomes come in contact with the heat, they dump their contents closest to their point of entry into the tumor -- the blood vessels around the tumor's edges. Since the body's normal tissues remain unheated, the small amount of drug that leaks out into normal tissues occurs over several weeks -- long enough for the liver and spleen to blunt its toxic side effects, he said.
According to Dewhirst, attacking a tumor's blood supply is a rapidly expanding field of cancer therapy. A number of clinical trials have shown that tumor cells will grow back after treatment if the tumor's blood vessel population remains intact. Even a few errant cancer cells that escape surgery or chemotherapy can regrow into a new tumor if there are blood vessels to sustain growth.
Some of the latest drugs on the market, including bevacisumab, are specifically designed to inhibit the growth of blood vessels that feed tumors, he said.
Heat also is a widely recognized enemy of cancer, Dewhirst said. Among its actions, heat increases the rate at which cancer cells absorb drugs. Heat increases oxygen levels within tumors, and oxygen is critical to the proper functioning of numerous chemotherapy agents. Heat also amplifies the level of genetic damage that chemotherapy inflicts on cells by inhibiting enzymes that normally repair this genetic damage.
"Hyperthermia boosts the killing power of radiation and chemotherapy by up to 10 times greater than without heat," Dewhirst said. "Our goal in Duke's hyperthermia program is to harness heat in a precisely controlled manner so we can best target and destroy tumors while sparing healthy tissue from the toxicity of chemotherapy and radiation."