The most common primary brain cancer is glioblastoma, a highly aggressive and deadly form of tumor that kills about 95 percent of its victims within five years of diagnosis.
Like other brain cancers, it is extremely difficult to treat because glioblastomas are usually deeply embedded within healthy brain tissue and therefore nearly impossible to safely access. Chemotherapy drugs cannot reach these tumors because a membrane between the bloodstream and brain tissue, called the blood-brain barrier, blocks them.
The blood-brain barrier is a way for the brain to protect itself from potentially dangerous chemicals or contaminants that may travel through the bloodstream. Unfortunately, the barrier also locks out cancer-killing drugs.
But new research at the University of Virginia and Johns Hopkins University is beginning to demonstrate that a battery of innovative techniques may be able to break though the blood-brain barrier and someday allow the effective treatment of glioblastoma.
The National Cancer Institute at the National Institutes of Health this month awarded the researchers a $3.3 million, five-year grant to continue their work and perhaps bring potential treatments to clinical trials. Studies laying the foundation for the NIH grant were supported by The Focused Ultrasound Surgery Foundation and The Hartwell Foundation.
"We are developing methods to target and kill these tumors by delivering chemotherapeutic drugs across the blood-brain barrier directly to the tumors," said Richard Price, a biomedical engineering professor in U.Va.'s School of Engineering and Applied Science and research director of the Focused Ultrasound Center, who co-leads the research with colleagues at Johns Hopkins. "This would allow us to deliver high concentrations of chemotherapy to the tumors while using generally small doses that would provide less toxicity to the rest of the body."
The technique uses a combination of three technologies to treat the tumor: biodegradable polymer nanoparticles bonded to chemotherapy drugs, microbubbles and focused ultrasound.
The microbubbles – dissolvable gas bubbles about the size of red blood cells – are injected into the bloodstream along with a nanoparticle/drug combination. This combination circulates through the body but does not reach the brain tumor, the intended target, because of the blood-brain barrier.
But the researchers have discovered a method to get the drug across that dividing line. They aim a focused ultrasound beam at the brain tumor. The beam – which is an adjustable, high-frequency sound wave – "excites" the microbubbles as they pass through the bloodstream near the tumor site. The microbubbles oscillate and vibrate about a million times per second.
The mechanical action of the microbubbles opens pores in the barrier between the blood vessels and the brain tissue. The opened membrane allows the controlled-release drug-bearing nanoparticles – circulating in the bloodstream – to cross into the brain. Because the ultrasound is focused directly on the tumor, the crossover happens only at that site, delivering the drug specifically to the tumor.
"This is really exciting because it gives us a tool to put medicine into a region of tissue that was very hard to access before," Price said, "and it allows us to use less drug to get a positive effect, which in turn reduces the negative side effects of chemotherapy."
The therapy, with modifications, may also have future applications for delivering drugs and genes to the brain to treat various neurodegenerative diseases such as Parkinson's, Price noted.
The researchers will be refining their techniques in the coming years, looking for the most effective ratios of microbubbles, drug particles and sound frequencies to create a harmonized symphony that could eventually blast away at glioblastoma, currently one of the most untreatable of all cancers.
– By Fariss Samarrai