Berkeleyan

 

In tests on mice with colon cancer, a drug attached to a polyester polymer cured 100 percent of them, says chemistry professor Jean Fréchet . (Michael Barnes photo)

Polymer envelope makes anticancer drug more effective
Researchers at Berkeley, UCSF believe the treatment is also potentially less toxic than commonly used liposomal drugs

By Robert Sanders, Public Affairs | 16 November 2006

Anticancer drugs are often highly toxic when delivered straight, but "wrapping" them inside larger molecules can lessen the side effects as well as make them more effective, according to a new study by researchers at Berkeley and UC San Francisco.

In recent experiments, a powerful cancer drug, doxorubicin, enveloped in a large polymer produced a 100 percent cure in mice with induced colon cancer, while all mice treated only with doxorubicin died. The doxorubicin-polymer combination proved as effective as a liposomal therapy - doxorubicin encapsulated in fat bubbles called liposomes - now used to treat several types of cancer in humans.

"There's nothing better than comparing a drug against what works in people, and in our tests in mice the new technique cured 100 percent of the mice, performing at least as well as the liposomal drug," says Jean Fréchet , professor of chemistry and chemical engineering and a researcher at Lawrence Berkeley National Laboratory. "We think the new technique has many advantages over liposome delivery."

Fréchet's colleague Frank Szoka, professor of pharmaceutical chemistry at UCSF and developer of the liposome-encapsulated doxorubicin, agrees.

"The dendrimer is as good as Doxil," he says, referring to the trade name of the doxorubicin-filled liposomes, which are approved for treatment of ovarian cancer and Kaposi's sarcoma. "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.

The idea of attaching bulky molecules to smallish drugs has fueled a lot of polymer research in the past 30 years, based on expectations that the larger molecules will remain in the blood for longer periods, allowing more time for them to infiltrate tumors to deliver a lethal dose. Theoretically, the larger molecules also would be less likely to slip through tightly knit blood vessel walls into healthy tissue, though still able to seep into cancerous tissue through their poorly built and leaky blood vessels.

"This way, you can target fast-growing tumors, like colon cancer, that have lots of leaky vasculature," Fréchet says. "As a result, the tumors accumulate the drug, but very little is taken up by other tissues."

Most chemists working in this area have focused, however, on attaching long-chain polymers to drugs, which requires costly synthetic chemistry. In addition, the polymer-drug combinations haven't behaved as predicted, and the chemical upon which most of these polymers are based - methacrylate - does not degrade in the body, which means it accumulates until eliminated by the kidneys.

Fréchet, however, saw an advantage with branching polymers instead of linear polymers. Called dendrimers because of their tree-like structure, they don't pass through filtration pores in the kidney - for the same reason that it's hard to force a tree branch though a hole. Tests show a half-life in the body of up to 30 hours, versus a few minutes for pure doxorubicin. A linear polymer with the same half life would be impractical, Fréchet said.

In addition, Fréchet based the dendrimer polymers on a chemical structure, a polyester, that is degraded naturally inside the body, which prevents its accumulation.

"Our contribution to this field was to recognize that polymer architecture makes a difference, and Jean's contribution was to recognize that polyester is a great backbone for doing this," Szoka said.

Fréchet and his graduate students synthesized a branching polyester polymer they refer to as a "bowtie" dendrimer because it has two halves that branch out from a center where they're tied together. The team chemically attached up to 32 doxorubicin molecules to one side of the bowtie, and a smaller number of linear chains to the other half, which wrapped around the package like a hairball, protecting the drug.

The mice were injected with colon-cancer cells and, several days later, with doxorubicin, doxorubicin-dendrimer, or Doxil. Though the latter two cured the mice, the group did not address long-term toxicity, which would require tests in larger animals. Doxorubicin is known to be toxic to the heart after repeated use, though liposome encapsulation seems to prevent this.

"Much less drug goes to the heart with the dendrimer and the liposome, so I would predict there would be much less cardial toxicity with the dendrimer also," Szoka said.

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. Thus, attachment to the dendrimer considerably reduces its side effects.

One big disadvantage of the dendrimer is that it requires laborious synthesis, but Fréchet already is at work on a new chemical process that could solve that problem, making synthesis relatively inexpensive.

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.

"Liposomes also can break in the bloodstream, increasing the chance of side effects," Fréchet says. "The doxorubicin dendrimer has little or no impact until it penetrates a cell, which eliminates the chance of drug side effects."

While Fréchet and Szoka pursue research on the new dendrimer-doxorubicin compound, they are looking at other drugs that could be delivered via dendrimers. It may even be possible to attach a cocktail of drugs to a single dendrimer so the drugs can be delivered together.

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