Breakthrough allows drug delivery for brain diseases and cancers.
Cornell researchers have discovered a way to open one of the major barriers to the brain, called the blood brain barrier (BBB), which prevents the entry of therapies to treat brain disorders, such as Alzheimer’s disease.
The finding also has implications for treating all chemotherapy-resistant cancers.
For a century now, a major challenge in the treatment of diseases of the brain has been discovering how to safely deliver drugs across the BBB. The BBB is composed of a layer of specialized cells, called endothelial cells, which line the brain’s blood vessels and safeguard the brain from unwanted substances. These cells also selectively allow entry of molecules needed for brain function, such as amino acids, oxygen, glucose and water.
Cornell researchers report that an FDA-approved drug called Lexiscan, which is used in heart imaging, activates receptors – called adenosine receptors – that are expressed on these BBB cells.
“We can open the BBB for a brief window of time, long enough to deliver therapies to the brain, but not too long so as to harm the brain. We hope in the future, this will be used to treat many types of neurological disorders,” said Margaret Bynoe, associate professor in the Department of Microbiology and Immunology in Cornell’s College of Veterinary Medicine. Bynoe is senior author of the study appearing April 4 in The Journal of Clinical Investigation. Do-Geun Kim, now a postdoctoral associate in Bynoe’s lab, is the paper’s first author.
The researchers were able to deliver chemotherapy drugs into the brains of mice, as well as large molecules, like an antibody that binds to Alzheimer’s disease plaques, according to the paper.
To test whether this drug delivery system has application to the human BBB, the lab engineered a BBB model using human primary brain endothelial cells. They observed that Lexiscan opened the engineered BBB in a manner similar to its actions in mice.
Bynoe and Kim discovered that a protein called P-glycoprotein is highly expressed on brain endothelial cells and blocks the entry of most drugs delivered to the brain. Lexiscan acts on one of the adenosine receptors expressed on BBB endothelial cells specifically activating them. They showed that Lexiscan down-regulates P-glycoprotein expression and function on the BBB endothelial cells. It acts like a switch that can be turned on and off in a time dependent manner, which provides a measure of safety for the patient.
“We demonstrated that down-modulation of P-glycoprotein function coincides exquisitely with chemotherapeutic drug accumulation” in the brains of mice and across an engineered BBB using human endothelial cells, Bynoe said. “The amount of chemotherapeutic drugs that accumulated in the brain was significant.”
In addition to P-glycoprotein’s role in inhibiting foreign substances from penetrating the BBB, the protein is also expressed by many different types of cancers and makes these cancers resistant to chemotherapy.
“This finding has significant implications beyond modulation of the BBB,” Bynoe said. “It suggests that in the future, we may be able to modulate adenosine receptors to regulate P-glycoprotein in the treatment of cancer cells resistant to chemotherapy.”
Because Lexiscan is an FDA-approved drug, ”the potential for a breakthrough in drug delivery systems for diseases such as Alzheimer’s disease, Parkinson’s disease, autism, brain tumors and chemotherapy-resistant cancers is not far off,” Bynoe said.
Another advantage is that these molecules (adenosine receptors and P-glycoprotein are naturally expressed in mammals. “We don’t have to knock out a gene or insert one for a therapy to work,” Bynoe said.
Funding: The study was funded by the National Institutes of Health and the Kwanjung Educational Foundation.
Source: Krishna Ramanujan – Cornell University Image Source: The image is credited to Do-Geun Kim, Margaret S. Bynoe/JCI. Original Research: Full open access research for “A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrier” by Do-Geun Kim and Margaret S. Bynoe in Journal of Clinical Investigation. Published online April 4 2016 doi:10.1172/JCI76207
A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrier
The blood-brain barrier (BBB) protects the brain from toxic substances within the peripheral circulation. It maintains brain homeostasis and is a hurdle for drug delivery to the CNS to treat neurodegenerative diseases, including Alzheimer’s disease and brain tumors. The drug efflux transporter P-glycoprotein (P-gp) is highly expressed on brain endothelial cells and blocks the entry of most drugs delivered to the brain. Here, we show that activation of the A2A adenosine receptor (AR) with an FDA-approved A2A AR agonist (Lexiscan) rapidly and potently decreased P-gp expression and function in a time-dependent and reversible manner. We demonstrate that downmodulation of P-gp expression and function coincided with chemotherapeutic drug accumulation in brains of WT mice and in primary mouse and human brain endothelial cells, which serve as in vitro BBB models. Lexiscan also potently downregulated the expression of BCRP1, an efflux transporter that is highly expressed in the CNS vasculature and other tissues. Finally, we determined that multiple pathways, including MMP9 cleavage and ubiquitinylation, mediated P-gp downmodulation. Based on these data, we propose that A2A AR activation on BBB endothelial cells offers a therapeutic window that can be fine-tuned for drug delivery to the brain and has potential as a CNS drug-delivery technology.
“A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrier” by Do-Geun Kim and Margaret S. Bynoe in Journal of Clinical Investigation. Published online April 4 2016 doi:10.1172/JCI76207