Tiny Lipid Balloons Curb Taxol's Toxicity

BUFFALO, N.Y. -- A new drug-delivery system for the anticancer drug, taxol, has allowed researchers to control resistant tumor growth in animals with doses of the drug that would be lethal if delivered using traditional methods.

Reported by scientists at the University at Buffalo and Roswell Park Cancer Institute in the Dec. 15 issue of Cancer Research, the study demonstrates that using microscopic lipid balloons, called liposomes, to deliver taxol may overcome some of the major obstacles to more effective use of taxol in fighting cancer.

Approved by the Food and Drug Administration for the treatment of ovarian cancer, taxol is one of the only treatment options for tumors that have grown resistant to conventional chemotherapies for ovarian cancer.

But the current method of administering taxol is not without its drawbacks, according to the Buffalo scientists, whose work is funded by the National Cancer Institute.

"Taxol has two problems," said Robert M. Straubinger, Ph.D., UB assistant professor of pharmaceutics and lead author of the study. "The drug itself is toxic and the solvent in which it is administered is also toxic."

The experiments showed that liposomes allowed taxol to be administered rapidly and in doses between 2 and 7 times larger than those the animals would have been able to tolerate as free drug.

"We're quite encouraged," said Straubinger. "By encapsulating taxol in liposomes, we have caused a marked decrease in toxicity and increased the drug's potency."

Not long ago, scientists were scrambling to find a way to synthesize taxol, which is harvested from the Pacific yew tree. But even after overcoming that major hurdle, obstacles remain.

Because it is virtually insoluble in water, taxol must be administered intravenously in an oily solution composed of a chemically modified castor oil and ethyl alcohol. If administered quickly, this solvent induces life-threatening symptoms that resemble anaphylactic shock. So taxol must be administered intravenously over a prolonged period of time, from 3 to 24 hours per dose.

"Right now, patients who take taxol have to be treated heavily with antihistamines and steroids," said Straubinger. "That controls the side effects, but some of these supplementary drugs may interfere with the same systems that transport or metabolize taxol within the body."

The chief advantage of liposomes, he explained, is that while they are essentially fat-soluble, they are also very stable in water. Thus, they provide a way to dissolve fat-soluble drugs in the watery environment of the body.

"Liposomes are particles with an oily core, and a fat-soluble drug like taxol tends to stay with them," said Straubinger. "As a result, we have reduced the massive wave of free drug that causes some of the side effects."

The UB researchers compared the conventional form of taxol against taxol in liposomes using animals with colon tumors. While taxol has not been effective against such cancers, the researchers decided to use these animals specifically because of the cancer's insensitivity to taxol.

One set of animals was given taxol encapsulated in liposomes, while the second was given free taxol, administered in the same solvent that is currently used.

"We were able to see control of tumor growth in animals given multiple injections of liposomes containing 40 milligrams of taxol per kilogram of body weight," said Straubinger. "If you gave that amount as free drug, it would have killed the animals. But in liposomes, it didn't; it just controlled the tumors nicely."

On the other hand, he said, the tumors in animals who received free drug could not be controlled at any dose of taxol.

"With the liposomes, we administered the dose all at once but we believe the drug was released slowly into the circulation, thus reducing the toxicity," said Straubinger.

The group is evaluating the activity of the liposome formulation against ovarian and breast tumors in animal models, since those tumors are the ones in which taxol has shown the greatest activity.