Novel Approach to Delivering Drugs Across the Blood-Brain Barrier to Treat Brain Tumors

Researchers have demonstrated in mice a new approach to delivering drugs across the blood-brain barrier to treat tumors that cause aggressive and deadly brain cancer.

In a new study, researchers show how a modified peptide, in mice, helps an anti-cancer drug cross the blood-brain barrier, which is known to be extremely difficult to penetrate and is therefore a massive obstacle to the treatment of brain tumours. The study was published online ahead of the December issue of Controlled Release Diary.

“We were not only able to get a drug into the brain, but to deliver it at a concentration that should be able to kill tumor cells,” said Sean Lawler, study author and associate professor of pathology and of Laboratory Medicine at Brown University, whose laboratory studies therapeutic approaches for the treatment of brain cancer.

Malignant brain tumors are among the deadliest forms of cancer, as well as the most difficult to treat. Glioblastoma is the most common malignant brain cancer -; it is very aggressive and most patients live only about 15 months after diagnosis. Despite the poor prognosis, Lawler said, there has been frustratingly little progress in treating glioblastoma and improving chances of survival over the past 20 years.

We believe this is an important finding that could ultimately inform new approaches to treating people facing some of the most serious brain cancer diagnoses.”

Sean Lawler, study author and associate professor of pathology and laboratory medicine at Brown University

One of the challenges in treating brain cancer, Lawler said, is getting therapeutic substances across the blood-brain barrier, a network of blood vessels and tissue made up of closely spaced cells that protects the brain from harmful substances. When it comes to cancer drugs, the blood-brain barrier does its job almost too well: cancer drugs cannot penetrate the barrier in sufficient quantities to have a therapeutic effect on tumors. Even drugs that have been shown to be effective against other types of cancers have not shown much effect on brain cancer -; probably because the blood-brain barrier is getting in the way.

“The question became, ‘How can we get more drug into the brain tumor to improve treatment outcomes?’ Legorreta Cancer Center. The Brown researchers collaborated on the study with a team from the Massachusetts Institute of Technology led by study author and professor of chemistry Bradley Pentelute.

The researchers focused on a type of peptide, or chain of amino acids linked by chemical bonds, that has an intrinsic ability to cross membranes and penetrate tissues. They modified the peptide by creating a staple between the amino acids in the sequence, which helped fortify and stabilize the peptide, and incorporated fluorine molecules. The collaborative research team had previously shown that this design could improve penetration of the peptide across the blood-brain barrier.

“We had this improved peptide that was not only more efficient at crossing the blood-brain barrier, but also could last longer in the body,” Lawler said. “And then we were able to hook it up to a cancer drug and test it in mouse models of glioblastoma. That was our big step forward.”

The researchers saw an opportunity, said Jorge L. Jimenez Macias, study author and postdoctoral fellow in Lawler’s lab.

“This new technology allowed us to test drugs against brain cancer that had not been used before against glioblastoma because they could not cross the blood-brain barrier,” said Jimenez Macias.

The researchers set up a preclinical trial -; basically a clinical trial in mice instead of humans. They used a drug control with the peptide and tested it against the drug with the enhanced barrier-penetrating macrocyclic peptide (called M13) in mice with brain tumors. Subsequent experiments were conducted to assess the concentration of drugs needed to kill tumor cells, as well as to understand how to deliver the drug at a safe level in a way that will not harm mouse patients. When these variables were tested, the researchers conducted a treatment study.

Study results showed that cell death due to the cell-penetrating macrocyclic and enhanced M13 peptide was observed primarily in tumor cells, not in healthy regions of the brain. This is the first time researchers have demonstrated how to use this modified peptide delivery system to deliver cancer drugs to the brain in the context of disease, Jimenez Macias said.

“We have shown for the first time that binding an anticancer drug to a cell-penetrating macrocyclic peptide leads to an effective dosage in mice several times higher than the drug alone, which can significantly prolong survival.” , said Jiménez Macias.

According to the study, the survival rate of mice treated with the improved peptide increased by 50%.

Lawler expressed optimism for future studies.

“It’s just the first attempt,” Lawler said. “We believe that with further optimization and adjustments to the drug and delivery system, we should be able to improve treatment and survival rate quite significantly.”

In addition to Brown University and the Massachusetts Institute of Technology, study collaborators included researchers from the Harvey Cushing Neuro-Oncology Laboratories in the Department of Neurosurgery at Brigham and Women’s Hospital and Harvard Medical School; the Free University of Brussels in Brussels, Belgium; and National Cheng Kung University in Taiwan.

The work was supported by the National Cancer Institute (R01-CA237063, R50-CA243706-02), the National Science Foundation (#1122374), the National Institute of Environmental Health Sciences (P30-ES00210), and the National Institutes of Health (R01-CA080024, P42-ES027707 and P30-ES002109).