Molecular envelopes help medicines penetrate multidrug-resistant cancer cells

SAN DIEGO, April 5 - Researchers believe they have found a way to defeat the multidrug resistance of many cancer cells and to dramatically reduce some of the undesirable side effects of chemotherapy. Based on work with cell lines, they claim that encasing therapeutic drugs in a polymer micelle - a molecular envelope - increases the uptake of the drugs by the resistant cancer cells. The findings were presented today at the 221st national meeting of the American Chemical Society, the world's largest scientific society.

Lead researcher Natalya Rapoport, Ph.D., of the University of Utah in Salt Lake City, cautions that animal studies have just started and that any possible cancer treatment based on the findings would be years away.

Rapoport uses a particular type of polymeric micelle because of its stealthiness. Pluronic micelles, as they are known, are virtually invisible to the body's immune system, which permits them to move undetected through the bloodstream to the tumor cells, she explained.

"Our idea is to encapsulate drugs in polymeric micelles, wait for their accumulation at the tumor, and then trigger drug uptake at the tumor site by focused ultrasound," Rapoport said. Ultrasound pokes temporary holes in the cell membrane that allow micelles to sneak in.

"Our goal is not only to target drug to tumor but to overcome drug resistance," Rapoport said. Previous researchers have shown that drugs administered together with Pluronic unimers - the molecules that make up Pluronic micelles - have a greater effect in multidrug resistant tumor cells than in other cancer cells. Other scientists have demonstrated that ultrasound increases drug uptake and that molecular envelopes can reduce misdelivery to noncancerous cells. But Rapoport is the first to show these strategies can be combined to specifically target multidrug resistant tumor cells.

Multidrug resistance (MDR) is one of the key roadblocks to effective chemotherapy. A few types of cancer are nearly always multidrug resistant: bladder cancer, for example - the seventh most common cancer in the United States, according to the American Cancer Society - is notoriously unresponsive to chemotherapy. Rapoport says it's possible her technique could one day be used to treat bladder cancer.

Micelle-encapsulated drugs not only bypass multidrug resistance, they are dramatically more potent in MDR cells. Rapoport hypothesizes that, once inside a cell, the molecules in the micelle interfere with the cell's ability to produce energy, intensifying the effect of the drugs. Reducing the cells' energy level is particularly damaging to MDR cells because they need extra energy to pump away unwanted drugs. "We have some experimental confirmation that the pump is paralyzed by micelles," she said. "But this isn't completely proven yet."

Another benefit of using micelles to target tumor cells is fewer undesired side effects. "When a drug is encapsulated in micelles, its uptake by healthy cells is substantially decreased, which prevents unwanted interaction with healthy tissue," Rapoport said.

"In contrast, the uptake by MDR cells is enhanced, which allows sufficient drug to get in and attack the cell's machinery," she added.

Rapoport noted that it is "unavoidable" that the drug will find its way into some noncancerous cells. "Some of the micelles will be taken up by normal cells, but it's three-fold to ten-fold less than what you'd have if you had the drug by itself, depending on what drug you're using," Rapoport said.

Rapoport, whose work is funded by the National Institutes of Health, has just started animal studies.

The poster on this research, PMSE 540, will be presented at 9:20 a.m., Thursday, April 5, at the San Diego Marriott, San Diego B, during the symposium, "Advances in Controlled Drug Delivery."

Natalya Rapoport is a professor in the department of bioengineering at the University of Utah in Salt Lake City, Utah.

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