A new method of delivering drugs to malignant brain tumors

The researchers demonstrated a new method in mice to treat tumors
that cause aggressive, deadly brain cancers that can be administered through the blood-brain barrier.

In a new study, researchers show how a modified peptide helps an anti-cancer drug cross the blood-brain barrier in mice
.
It is well known that the blood-brain barrier is extremely difficult to penetrate, thus becoming a huge obstacle
to the treatment of brain tumors.
The study was published
online ahead of the December issue of the Journal of Controlled Release.

"Not only can we get the drug into the brain, but we can also release it at a concentration sufficient to kill tumor cells," said Sean Lawler, an associate professor of pathology and laboratory medicine at Brown University whose lab studies treatments
for brain cancer.

Malignant tumors of the brain are among the deadliest cancers and the most difficult to treat
.
Glioblastoma is the most common malignant brain cancer – it is so aggressive that most patients only survive about 15 months
after diagnosis.
Despite the poor prognosis, Lawlor said, it's discouraging that little progress has been made in treating glioblastoma and improving survival chances over the past 20 years
.

"We think this is an important finding that could ultimately lead to new ways
to treat some of the most serious brain cancer diagnoses," Lawlor said.

Lawlor said one of the challenges in treating brain cancer is getting therapeutic substances to pass through the blood-brain barrier, a network of blood vessels and tissues made up of closely spaced cells that protect the brain from harmful substances
.
When it comes to anti-cancer drugs, the effect of the blood-brain barrier is almost too good: anti-cancer drugs cannot penetrate the blood-brain barrier in sufficient quantities to have a therapeutic effect
on tumors.
Even drugs that have been shown to be effective for other types of cancer have not shown much effect against brain cancer — possibly because the blood-brain barrier is holding it
back.

"The question becomes, 'How do we get more drugs into brain tumors to improve treatment?'" Lawler, who is co-leader
of the Central Nervous System Cancer Translational Disease Research Group at the Legorreta Cancer Center at Warren Alpert College of Medicine.
Researchers at Brown University conducted the study in collaboration with an MIT team led by study author Bradley Pentelute, a professor of chemistry
.

The researchers focused on a peptide, a chain of amino acids linked by chemical bonds, that has the intrinsic ability to
penetrate cell membranes and penetrate tissues.
They modified the peptide by creating a short chain between amino acids in the sequence, which helps strengthen and stabilize the peptide, and added fluorine molecules
.
The collaborative research team has previously shown that this design can improve the ability of peptides to penetrate across the blood-brain barrier
.

"We have this enhanced peptide, which not only passes the blood-brain barrier better, but also lasts longer in the body
," Lawlor said.
"We were then able to attach it to a cancer drug and test it
on a mouse model with glioblastoma.
" This is an important step
forward for us.
”

Jorge L.
Jimenez Macias, a postdoc in Lawlor's lab and author of the study, said the researchers saw an opportunity
.

Jimenez Macias said: "This new technique allows us to test drugs for brain cancer that were not previously used to treat glioblastoma because they cannot cross the blood-brain barrier
.
"

The researchers conducted a preclinical trial — basically in mice rather than humans
.
They used a drug control containing the peptide in mice with brain tumors and compared
it with a drug containing an enhanced macrocyclic barrier-penetrating peptide (M13).
Experiments were then conducted to assess the concentration of drugs needed to kill tumor cells and to understand how to administer
at safe levels without harming mouse patients.
After testing these variables, the researchers conducted a treatment study
.

The findings suggest that cell death due to macrocyclic cell penetration peptide M13 enhancement occurs mainly in tumor cells rather than in healthy areas of
the brain.
Jimenez Macias said this is the first time researchers have demonstrated how to use this modified peptide delivery system to deliver cancer drugs to the brain
in case of disease.

Jimenez Macias said: "We have shown for the first time that linking anticancer drugs to macrocyclic cell penetrating peptides can make the effective dose in mice many times higher than that of drugs alone, which can significantly prolong survival
.
"

The results showed that the survival rate of mice treated with fortified peptides increased by 50%.

Lawlor expressed optimism
about future research.

"It's just the first attempt
," Lawlor said.
We believe that by further optimizing and adapting drugs and delivery systems, we should be able to significantly improve treatment and survival
.
and/or members of the Scientific Advisory Board
.