OCT 24, 2016 2:47 PM PDT

Drug Gets Makeover to Bypass the Blood-Brain Barrier

WRITTEN BY: Xuan Pham
The blood-brain barrier is a formidable defense for the protection of one of the most critical organs in the body – the brain. Yet, while this barrier keeps out pathogens and other invaders, it also prevents life-saving drugs from reaching the brain, severely limiting the available therapies for brain-related diseases, such as brain cancer. Now, working with a potent anticancer drug that’s far too damaging for the rest of the body save for the brain, Johns Hopkins researchers learned how to bypass the blood-brain barrier.
 
The anticancer drug is known as 6 diazo-5-oxo L norleucine (DON), and it’s quite effective at shrinking tumors by blocking the cancer cell’s ability to use the amino acid glutamine. However, this property raises the toxicity of DON, especially in the gastrointestinal system, where glutamine is heavily consumed. But what if researchers could confine DON to one organ that’s not so dependent on DON?
 
"We wondered whether we could make a safer and more tolerable form of DON by enhancing its brain penetration and limiting its exposure to the rest of the body and, thus, toxicity," said Barbara Slusher, professor of neurology, medicine, psychiatry, neuroscience and oncology at the Johns Hopkins University School of Medicine, and the study’s senior author.
 
Based on collaboration with researchers at the Johns Hopkins Kimmel Cancer Center, the team zeroed in on tumors in the brain. "A tumor uses aggressive metabolism to grow, sucking up all the surrounding nutrients, which leads to a very oxygen-poor, acidic environment that is not conducive to cancer-killing immune cells," said Jonathan Powell, an immunologist at the Kimmel Cancer Center. Drugs that block glutamine could provide the edge needed for immunotherapy drugs to work.
 

But then, the question became how to get DON into the brain? The team tackled this by making the drug more lipid soluble, a key property that helps DON slip past the blood-brain barrier. Once inside the brain, the drug is converted back to its potent form to attack cancer.
 
Importantly, the team demonstrated the effectiveness of this technique in live monkey studies. In monkeys that were given the altered derivative, the team found the drug was more highly concentrated in the brain – the target of the drug. By contrast, monkeys given the unaltered version of the drug had 7 times the drug concentration in their blood, confirming the inability to localize to a certain target.
 
"We showed that we can modify these drugs to have further specificity to target the brain and limit toxicity to the rest of the body," says Slusher. "This strategy can potentially be used to develop tailored drugs for different cancers."
 
The team hopes to combine the new formulation of DON with other immunotherapy agents to have new synergistic anticancer weapons. "The hope is to enhance certain immunotherapy drugs by adding such glutamine antagonists," says Powell. 

Additional sources: Johns Hopkins University
About the Author
  • I am a human geneticist, passionate about telling stories to make science more engaging and approachable. Find more of my writing at the Hopkins BioMedical Odyssey blog and at TheGeneTwist.com.
You May Also Like
APR 14, 2021
Clinical & Molecular DX
AI-Powered Imaging System Can Tell If a Patient Is Cancer-Free
APR 14, 2021
AI-Powered Imaging System Can Tell If a Patient Is Cancer-Free
A patient undergoes chemotherapy and radiation for rectal cancer. How do doctors know whether all the malignant tissue h ...
APR 27, 2021
Clinical & Molecular DX
No Batteries: Health Sensor Harvests Biomechanical Energy
APR 27, 2021
No Batteries: Health Sensor Harvests Biomechanical Energy
An international team of researchers has developed a wearable health monitor that works without the need for batteries. ...
JUL 15, 2021
Clinical & Molecular DX
Childhood Lead Exposure Influences Personality in Adulthood
JUL 15, 2021
Childhood Lead Exposure Influences Personality in Adulthood
Exposure to toxic chemicals in childhood could have unlikely effects on personality, and behavioral traits in adulthood, ...
AUG 04, 2021
Genetics & Genomics
Variants May Predict Which Young People Are at Risk for Severe COVID-19
AUG 04, 2021
Variants May Predict Which Young People Are at Risk for Severe COVID-19
While people carry mostly the same genes, there are many small changes in the sequences of those genes, and small variat ...
AUG 17, 2021
Clinical & Molecular DX
Delays in Breast Cancer Diagnoses Among Black Women
AUG 17, 2021
Delays in Breast Cancer Diagnoses Among Black Women
Thanks to breakthrough diagnostic technologies, we can now catch the early warning signs of breast cancer much faster th ...
SEP 09, 2021
Clinical & Molecular DX
A Drug Test for Synthetic Cannabis Use
SEP 09, 2021
A Drug Test for Synthetic Cannabis Use
Designer drugs are synthetic analogs of prohibited substances such as cocaine and LSD made in clandestine laboratories a ...
Loading Comments...