About the Blood Brain Barrier (BBB)

About the Blood Brain Barrier (BBB)

The Blood-Brain Barrier and Drug Delivery

William, Olbricht, PhD, Scientific Founder, Alcyone Lifesciences

The blood-brain barrier (BBB) refers to the physical and molecular characteristics of cerebral blood vessels that provide a selective “barrier” against mass transfer of many molecules, including potentially dangerous ones, from the bloodstream to the brain.  The BBB is essential for the brain to maintain a favorable environment for neurons and other cells to carry out their normal functions.

The BBB relies on some unique properties of the endothelial cells that line the inner walls of cerebral blood vessels.  Endothelial cells in the brain are different from endothelial cells elsewhere in the body.  Brain endothelial cells lack small openings in their membranes that are common in membranes of endothelial cells elsewhere in the body.  Proteins embedded in brain endothelial cell membranes pull together adjacent endothelial cells to form “tight junctions” between the cells.  As a result, only the smallest molecules can move from the blood to the surrounding tissue by diffusing through the narrow gaps between endothelial cells in the brain.  The barrier formed by the endothelial cells is supported by an assortment of other cells, including pericytes and astrocytes, which help keep the BBB in tact regardless of pressure changes inside the blood vessels.  In addition, brain endothelial cells exhibit low levels of transcytosis, which refers to mass transfer of compounds across cells in small packets called vesicles.  Although the BBB restricts mass transfer from the blood to the brain, it does not inhibit transfer of molecules from the brain back into the blood stream.  In fact, transporter molecules such as p-glycoproteins, embedded in the endothelial cell membranes, pump a broad array of molecules from the brain to the blood stream.  Thus, the BBB has a two-fold effect on drug delivery to the brain.  It prevents systemic delivery of many therapeutics and it removes therapeutics that are delivered to the brain by other means.

The BBB Limits Systemic Delivery of Many Therapeutic Compounds

By regulating exchange of compounds between the blood and the brain, the BBB helps maintain homeostasis in the brain, but the BBB also poses challenges to deliver therapeutics to treat a variety of neurological disorders such as Parkinson’s disease, epilepsy and cancer.

Glioblastoma multiforme (GBM) is a primary brain tumor that forms from a malignancy of glial cells, which are a class of cells that support neurons.  GBM does not metastasize to other organs, but malignant cells from a GBM tumor typically migrate into surrounding healthy brain tissue.  The prescribed treatment for GBM usually involves surgical removal of the main tumor mass.  However, surgery cannot remove the cancerous cells that have infiltrated surrounding tissue, which means the disease recurs after surgery, leading to a poor prognosis for many patients.  The average survival time after diagnosis of GBM is about a year.

Systemic delivery of anti-cancer drugs, such as bis-chloroethynitrosourea (BCNU), which blocks DNA replication and transcription, is ineffective.  The dosage that would be required in the blood stream to overwhelm the BBB would be toxic to other organs.  Systemic delivery of some of the most promising modern therapeutics to treat GBM, including proteins, monoclonal antibodies, viral vectors, and drug-carrying nanoparticles, also is ineffective, because these constructs are too large to cross the BBB., new methods are required To deliver these compounds to the brain by enhancing transport across the BBB or by circumventing the BBB altogether.

Circumventing the BBB

One way to circumvent the BBB is to deliver drugs directly into the brain parenchyma (intraparenchymal drug delivery).  Although the approach is invasive, it is sometimes coupled to other procedures, and it can be used to deliver almost any drug of potential benefit.

The FDA in 1996 approved a new product for the treatment of GBM that consists of a small polymeric wafer loaded with BCNU.  After a tumor is removed surgically, several wafers are placed against the walls of the resection cavity.  The wafers slowly release BCNU into the surrounding tissue, achieving local concentrations that exceed by far the maximum concentration that could be delivered safely via the blood stream.  Approval of this product was based on results showing increased survival at six months by about 50% and an increase in median survival by two months.

BCNU released from the wafers moves through brain tissue by diffusion.  However, the diffusing BCNU molecules can be removed from the brain by a variety of mechanisms, including clearance back into the blood stream by the endothelial transporters mentioned earlier.  The distance that the BCNU penetrates into the tissue is determined by relative rates of diffusion and elimination.  In this case, it turns out that the penetration of BCNU is only a few millimeters, which is insufficient to eliminate malignant cells that have migrated farther into the surrounding tissue.

A team at the NIH in the mid-1990s developed an alternative method called convection-enhanced delivery (CED).  In CED, fluid containing a therapeutic is pumped directly into brain tissue through a fine needle or cannula that is inserted into the brain through a small hole in the skull.  The fluid flows from the tip of the needle into the surrounding tissue and carries with it drugs that are dissolved in the infused fluid.  In this case, the motion of the drugs through the brain tissue is dominated by convection rather than diffusion.  If the rate of convection can be made large enough to overcome elimination, then the penetration of the drug into the surrounding tissue may be much greater than that obtained with diffusion-based delivery platforms.