After 10 years of trial and error, Yale bioengineers have developed a new approach to brain-tumor chemotherapy that could potentially extend the life spans of countless cancer patients.
The therapy — developed by Mark Saltzman, chemical and bioengineering professor — involves adding polyethylene glycol, a water-soluble polymer known as PEG, to the anti-cancer drug camptothecin. Early trials performed on rats with brain tumors have shown that conjugation with PEG allows the drug to penetrate farther into the brain and remain effective longer.
The team published its results in the November-December issue of “Bioconjugate Chemistry” magazine.
The new drug has the potential to increase treatment distance from a few millimeters to more than a centimeter — which may be large enough to prevent brain tumors from recurring, according to a University press release.
“We had been testing similar ideas for many years, but previous versions did not work as well,” Saltzman said. “But then we hit on this particular combination, which seemed to work very well.”
One traditional method of delivery involves surgically placing polymer implants containing the drug at the site of the tumor, but Saltzman said this approach is often ineffective because the drugs do not penetrate far enough and disappear too quickly to destroy the entire tumor.
The blood-brain barrier — which protects the brain from environmental toxins — is responsible for hindering the diffusion of anti-cancer drugs, medical oncologist professor Jill Lacy said.
“Many chemotherapy drugs that we use in oncology don’t penetrate across the barrier, so the brain is a sanctuary site for metastases,” she said. “It’s been a barrier to developing effective therapies for brain tumors.”
Tumors are also amorphous — which helps them avoid being cleared by the body’s immune system — and are therefore highly resistant to treatment, Biomedical Engineering professor Tarek Fahmy said. When traditional treatments are applied, the tumors tend to either expel the drugs or sequester them, instead of allowing the drugs to penetrate, he said.
The concept of conjugation with PEG is not especially new, Fahmy said. For example, Pegasus — a treatment for hepatitis C — consists of interferon coupled with PEG, which helps increase the circulation of numerous drugs.
“[Conjugation] is a very important way of keeping drugs circulating for a long period of time and allows them to diffuse on a larger spatial scale,” Fahmy said.
But Saltzman’s team was the first to use PEG as a way to deliver anti-cancer drugs to brain tumors, Saltzman said.
In the team’s experiments, conducted over approximately five years, researchers bonded PEG with camptothecin, encapsulated it in another polymer and implanted it into the subjects’ brains, he said. The drug was released in the brain gradually over time.
Saltzman’s next step, he said, is to try the approach on a variety of other animals within the next few months to ensure it works in the same way across species. After that, he said he hopes to perform clinical trials on humans and get the drug on the market, although that step may be several years away.
“It can take at least five to 10 years to start testing in people,” Saltzman said. “We worked on another [brain-tumor treatment] called Gliadel in the 1990s, and we went from testing to approval in a period of about eight years. If everything goes right, that kind of a timeline might work.”
Lacy said it would be premature to judge the long-term effectiveness of the treatment, but she said she is hopeful about the way the new approach overcomes traditional obstacles to brain-tumor chemotherapy.
“It’s interesting and promising, and it may have applicability,” she said. “And it’s potentially an improvement over the current polymer implants. It’s a good first start to getting at the difficulty of effective drug delivery to brain tumors.”
Saltzman’s research was funded by grants from the National Institutes of Health.