How a parasitic fish inspired a new way to get drugs into the brain
The blood-brain barrier normally blocks many types of drugs from entering the central nervous system, making it hard to treat brain disorders. Scientists from the University of Wisconsin-Madison and the University of Texas at Austin hope to solve that problem with the help of an unlikely ally: the jawless sea lamprey. And they have promising early evidence that a molecule derived from the creature could be used to ferry drugs directly to previously difficult-to-access diseased sites in the brain.
When the researchers combined the drug-delivery system they developed with an anti-cancer drug, they observed better treatment results in mice with brain tumors, according to a study published in the journal Science Advances. The team believes the findings offer hope for treating other brain disorders.
Despite its unattractive appearance and parasitic nature, the sea lamprey has a robust immune system similar to that of humans. But instead of making antibodies, the fish produces small defensive molecules called variable lymphocyte receptors (VLRs). It was these VLRs that served as the basis for the new drug delivery technology.
The blood-brain barrier is a natural defense mechanism that protects the brain from toxins or pathogens that are circulating in the blood. That prevents many types of molecules, including VLRs, from reaching the brain via the bloodstream. But when diseases are present, that can expose the “extracellular matrix,” a web of proteins and sugars that surrounds cells in the brain. A leaky extracellular matrix offers a unique entry point for the lamprey-inspired compounds.
“Molecules like this normally couldn’t ferry cargo into the brain, but anywhere there’s a blood-brain barrier disruption, they can deliver drugs right to the site of pathology,” said Eric Shusta, Ph.D., professor of engineering at the University of Wisconsin and the study’s senior author, in a statement.
Shusta’s team vaccinated lampreys and picked VLRs that bound tightly to the brain’s extracellular matrix. To test the benefits of the delivery system, the researchers decided to test it in a mouse model of the deadly brain cancer glioblastoma. They loaded the selected VLRs with Johnson & Johnson’s chemotherapy drug Doxil (doxorubicin). The combo significantly prolonged survival of the animals, the team reported.
The new approach boasts several advantages, the team said. First, because brain cells actively pump out many chemicals, targeting the matrix could facilitate the delivery of much higher doses of medicine than would be possible when aiming directly at brain cells.
“Similar to water soaking into a sponge, the lamprey molecules will potentially accumulate much more of the drug in the abundant matrix around cells compared to specific delivery to cells,” said study co-author John Kuo in the statement.
Secondly, the technique seems to steer clear of healthy tissues, which may reduce off-target adverse reactions. In mouse study, the researchers observed that the drug payload in the region of the tumors was 112-fold higher than it was in surrounding areas.
In the future, the researchers hope that the VLP-based molecules could be customized to carry medicines for other neurological diseases that need to pass through the blood-brain barrier. Alzheimer’s, multiple sclerosis, stroke and traumatic injuries are among such conditions, they said.
There’s also room to improve the glioblastoma treatment. As the invasive tumor margins generally reside behind an intact blood-brain barrier, “further work is needed to combine these VLRs with a therapeutic platform that is capable of spreading and inclusively targeting the clinically important invasive margin,” the scientists wrote in the study. They also envision using more targeted medicines to pair with the delivery system, such as Merck & Co.’s chemotherapy drug Temodar (temozolomide)—which is approved to treat brain cancer—or immune checkpoint inhibitors.