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Circumventing the Blood-Brain Barrier

by Peyton Shieh

Prof. James Rubenstein spoke today on “Drug Delivery to the Central Nervous System”. He is a physician-scientist at UCSF interested in delivering biologics and triggering immune responses that target brain cancer. One in six Americans suffer from some sort of brain-related disease, from Alzheimer’s to lymphoma to depression. Unfortunately, the blood-brain barrier represents a major barrier, in the literal sense, to the development of pharmaceuticals for the treatment of these diseases. The blood-brain barrier only allows relatively small, lipophilic drugs to access the brain from the bloodstream. For brain cancer, this means that potent chemotherapeutics like Taxol or biologics like Rituximab are rendered ineffective. A way to circumvent this barrier is the direct injection of active pharmaceutical agents into cerebrospinal fluid (CSF) to access the brain. To perform CSF-delivery, Prof. Rubenstein uses the Ommaya reservoir, a plastic pipette-like device that is connected to a metal catheter. This device is surgically implanted into the patient’s skull, with direct access to the lateral ventricles of the brain, major reservoirs of CSF. Prof. Rubenstein has shown that CSF-delivery can be successful in the treatment of brain lymphomas using the biologic Rituximab, yet further optimization of this strategy is still needed. One major limitation is that compounds delivered in the CSF have a very short resident half-
life, less than four hours, although the reasons behind this rapid clearance are not clear. A better understanding of the mechanisms of clearance, however, may allow for the optimization of therapeutics for CSF-delivery. Alternatively, this short half-life may be overcome through the use of a pump to continuously inject the drug into the patient using the Ommaya reservoir. While Prof. Rubenstein focused mostly on CSF-delivery, he briefly discussed other strategies for bypassing the blood-brain barrier. I found one strategy, using a hyperosmotic agent such as mannitol to bust through the blood-brain barrier, particularly interesting given its non-invasive nature. Mannitol non-selectively permeabilizes the blood-brain barrier, which can lead to side effects such as seizures or strokes. Designing a smarter hyperosmotic agent using the tools and strategies we’ve learned in our chemical biology course may allow for more selective permeabilization of this barrier to minimize the risk of side effects.

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