The main challenge in the treatment of cancers and other brain disorders is making sure that medicines reach their targets. A research team of clinician-scientists and biomedical engineers, from the University of Texas and Wisconsin-Madison, took molecules from an immune system of parasitic sea lamprey to deliver the anti-cancer drugs to brain tumors directly.
The results were published in the journal Science Advances.
Most medicines used currently target specific features inside or on individual cells in our body’s tissues and organs. The lamprey-derived molecules aim at a different target. This extra target is the extracellular matrix. It is a tangled mesh of sugars and proteins supporting and surrounding all the cells in the brain.
The team believed they could adapt and combine the molecules with a variety of other therapies. This would offer hope for the treatment of many brain ailments other than tumors including Alzheimer’s disease, sclerosis, and even traumatic injuries.
According to Eric Shusta, this set of targeting molecules appeared to be agnostic to the disease. They believed it was applicable as a platform technology across many conditions.
This technology took advantage of the fact that most diseases tamper with one of the body’s natural defense mechanisms. This is the blood-brain barrier lining the central nervous system’s blood vessels and protects the brain against potential threats like pathogens and circulating toxins.
Most drugs are not able to reach targets in the brain once injected into the bloodstream, including lamprey-derived molecules. This is because the blood-brain barrier prevents large molecules from leaving the brain’s blood vessels. In conditions like stroke, brain cancer, multiple sclerosis, and trauma, the barrier becomes leaky in and around the disease locations. This offers a unique entry point. It allows the matrix-targeting lamprey molecules access to the brain delivering drugs precisely on the target.
According to Shusta, such molecules are not usually able to take cargo to the brain but once there is a blood-brain barrier disruption, they are able to deliver drugs to the pathology site.
Effect on mice
With the knowledge that brain tumors cause the barrier to leak, the team linked the lamprey-derived molecules to a Food and Drug Administration-approved chemotherapy known as doxorubicin. This treatment prolonged mouse models’ survival of glioblastoma. This is an incurable brain cancer that afflicted Senators Ted Kennedy and John McCain.
The matrix-targeting technique means that many therapies could be linked to the lamprey-derived molecules. Researchers can combine these therapies with techniques that temporarily open the blood-brain barrier at certain brain sites.
John Kuo, a collaborator, said that the lamprey molecules could potentially accumulate more of the drug in the abundant matrix around cells compared to specific delivery to cells. In addition, the brain cells actively pump out many chemicals. This is a useful trick for protecting against toxic compounds.
Humans and lampreys have a similar immune system. However, lampreys produce small crescent-shaped defensive molecules known as VLRs instead of antibodies. The team “vaccinated” lampreys using the brain’s extracellular matrix components. They then searched through thousands of VLRs to find one which stuck to the brain matrix specifically.
The lamprey-derived molecules circulated within the body in the mouse studies. This targeted delivery is important in treating cancer since most therapies cause debilitating adverse reactions because of the indiscriminate effect on healthy cells.
The team plans to link the matrix-targeting molecules to additional anti-cancer drugs like immunotherapy agents which activate a patient’s immune system to destroy tumors. They also see hope in using the molecules to detect blood-brain barrier disruption. The team believes that many other brain medicines could be more effective if targeted to the matrix.
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The University of Wisconsin-Madison. (2019, May 15). Jawless fish take a bite out of the blood-brain barrier. ScienceDaily. Retrieved May 22, 2019, from www.sciencedaily.com/releases/2019/05/190515144003.htm