Imagine that you’ve been tasked with pulling off the ultimate heist, a George Clooney-level break-in to the most heavily guarded, impenetrable biological “bank”: the brain. The only problem with this particular stronghold is the balance of its input and output maintains life – and with the stakes being literal life and death, the defense mechanisms the body employs to limit delivery to the brain continue to obstruct treatment of neurological disorders.
The blood-brain barrier (BBB) is one of the best studied of these defense mechanisms. It consists of a tight layer of capillary endothelial cells that are held together by tight junctions in order to separate brain extracellular fluid (BECF) from the circulating blood. While “impenetrable” might seem hyperbolic – and in fact, the BBB allows for the passive diffusion of water, small gasses, and hydrophobic hormones necessary for proper neural function – its structure disallows the import of a wide array of microscopic objects. Efflux pumps such as P-glycoprotein (P-gp) litter the barrier acting like the strictest of bouncers to export toxins and drugs that manage to sneak through. How, then, do we selectively disrupt the BBB in order to deliver curative therapy to the brain?
Early strategies involved making drugs of interest more lipid-soluble. The endothelial cells lining the BBB are lipophilic, allowing for the penetration of hydrophobic molecules. One of the major downsides to this approach, however, is that all drugs of interest were now able to cross the lipid membranes of just about any tissue type in the body, leading to unwanted side effects. In response to this, research has focused on engineering artificial, carrier-pigeon-like constructs that bind to endothelial receptors and allow for effective transport. These molecular Trojan horses have shown promise and several clinical trials are proceeding with using specific receptor-mediated transport systems.
Focused Ultrasound (FUS) is a noninvasive, reversible, and exciting new technique that induces selective disruption of the BBB. The mechanism behind focused ultrasound is similar to using sunlight and a magnifying glass to burn a hole into the offending toy of your choice. In this scenario, the concentrated acoustic energy of the FUS is directed towards a focal spot in the brain. This energy interacts with previously administered, circulating microbubbles – a contrast agent commonly used in ultrasound imaging – causing them to oscillate. The force generated by their vibration leads to a temporary disruption of endothelial lining of the BBB, increasing its permeability. While the mechanics of the procedure sound simple, controlling the acoustic pressure in order to prevent vascular and surrounding tissue damage resulting from excessive force has only recently been determined. Coupling FUS with magnetic resonance imaging (MRI) allows for real-time monitoring and high-resolution 3D imaging of the tissue site during treatment. So far, the results are impressive.
In October of this year, for the first time ever, Magnetic Resonance-guided Focused Ultrasound Surgert (MRgFUS) was successfully employed to open the BBB in human patients. Michael Canney and his group at CarThera in collaboration with Alexandre Carpentier, a surgeon at Pitié-Salpêtrière in Paris, decided to test the technology on patients suffering from glioblastoma, a particularly nasty and aggressive type of brain tumor. Canney and his team used MRgFUS for two minutes at a time on each of four patients, which they approximated to correlate with a 6-hour increase in BBB permeability. A molecular marker included in the chemotherapy was shown to cross the BBB suggesting, they hoped, that the chemotherapy makes the journey across as well. The BBB remains an impressive force protecting us from all manner of bad guys and while it may take a little while longer before a change in the cancer and the long-term effects of the technique are reported, the safe and successful use of MRgFUS in human patients firmly establishes it as an exciting new technology for clinical treatment of neurological disorders.