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Fréchet helps develop new cancer therapeutic


Jean Fréchet (Michael Barnes photo)

Jean Fréchet, who holds the Henry Rapoport Chair in Organic Chemistry and also has an appointment chemical engineering, has developed a polymer that can wrap around molecules of potent anti-cancer drugs, making them more likely to reach tumor cells and less likely to damage other cells.

When injected into the bloodstream, molecules of the anti-cancer drug doxorubicin plummet through the body, often missing their intended target but damaging other cells before being rapidly excreted by the kidneys. When attached to a doxorubicin molecule, Fréchet's branching polymer, or dendrimer, acts like a parachute, allowing the drug to linger in the bloodstream and increasing the likelihood that it will be snagged by the messy vasculature of tumor cells.

In recent experiments, the polymer-enveloped doxorubicin produced a 100 percent cure in mice with induced colon cancer, while all mice treated with doxorubicin alone died. The doxorubicin-polymer combination proved as effective as the liposomal medication Doxil, the current standard.

"We think the new technique has many advantages over liposome delivery," says Fréchet. In Doxil, the liposomal drug, the doxorubicin is encapsulated in fat bubbles called liposomes. One advantage of the dendrimer over liposomes is that the therapy can be delivered via one injection, while liposome treatment is by intravenous infusion. Both deliver a higher dose of drug - three to four times as much - than can be achieved with doxorubicin alone, since the drug is so toxic.

Another advantage of the dendrimer is its stability, which allows the doxorubicin polymer to be dried and stored for long periods of time, then rehydrated. Liposomes have the disadvantage that they are fragile and have an 18-month shelf-life if frozen. For now, one disadvantage of the dendrimer is that it requires laborious synthesis, but Fréchet already is at work on a new chemical process that could make synthesis relatively inexpensive.

"Liposomes also can break in the bloodstream, increasing the chance of side effects," Fréchet said. "The doxorubicin dendrimer has little or no impact until it penetrates a cell, which eliminates the chance of drug side effects." Fréchet's colleague Frank Szoka, professor of pharmaceutical chemistry at UCSF and developer of Doxil, the liposome-encapsulated doxorubicin, agrees. "The dendrimer is as good as Doxil," says Szoka. "Doxil is a lot less toxic than doxorubicin, and I think the dendrimer will be a lot less toxic for many of the same reasons." Szoka is the scientific founder of Sequus Pharmaceuticals Inc., the Menlo Park company that invented the Doxil product.

Fréchet, Szoka and their colleagues reported their success in a paper appearing last week in the Online Early Edition of the Proceedings of the National Academy of Sciences.

The work is supported by the National Institutes of Health. Also coauthors on the PNAS paper are UC Berkeley chemistry graduate students Cameron C. Lee, Elizabeth R. Gillies, Megan E. Fox and Steven J. Guillaudeu, and Edward E. Dy of the UCSF Department of Biopharmaceutical Sciences and Pharmaceutical Chemistry.

Based in part on press release by Robert Sanders.

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