Bubbling Through the Blood Brain Barrier
by Jennifer Cortes
The blood brain barrier consists of tight junctions between the vascular endothelial cells that nourish neurons in the central nervous system. Tight junctions are a type of cell-to-cell adhesion that essentially eliminates gaps between adjacent cells, thereby preventing toxins in our blood from reaching and damaging the central nervous system. While the blood brain barrier (BBB) is essential for survival, its very nature complicates therapeutic drug delivery to the brain. Recent breakthroughs in ultrasound-activated microbubble technology offer a promising solution to breaking the barrier and treating brain disease.
To understand the mechanism of microbubbles, think Ms. Frizzle and her class’s voyage through Ralphie’s veins in the magic school bus. Microbubbles (MBs) are hydrophilic bubbles of gas that measure between one and four micrometers in diameter. MBs are injected into the bloodstream and, just like the magic school bus, they flow along the normal circulatory route. As they flow by a target region, near a tumor for example, they can be induced via ultrasound to oscillate.
As the bubbles oscillate, they exert a mechanical force on the blood brain barrier. As the vascular endothelial cells are pushed apart, the tight junctions that create the BBB are disrupted. In other words, the bubbles push against the blood vessel walls and create gaps between the cells lining the blood vessel. In effect, the BBB becomes more permeable to chemicals in the blood stream for approximately 6 hours, until the tight junctions are reformed.
Although the efficacy and safety of MBs have been proven in animal research studies, it was not until July that MBs were used for the first time in four cancer patients at Pitié-Salpêtrière Hospital in Paris. The patients had been diagnosed with recurrent glioblastoma, a highly malignant type of brain tumor. Glioblastomas reproduce rapidly as they are supported by an ample blood supply. The efficiency of chemotherapeutic drugs is hindered by their inability to cross the BBB and thus these patients were perfect candidates for MBs.
The ultrasound medical device used is called SonoCloud; it was designed by a Paris-based medical start-up company called CarThera. The ultrasound transducer is implanted into patients’ brains. The transducer transmits pulses of ultrasound to a small region of the brain measuring 1 cm by 5 cm. Once a month, the patients were given an injection of MBs along with a chemical marker, and the transducer was switched on for two minutes. The patients were then given IV injections of Carboplatin, a commonly used chemotherapy drug that kills cancerous cells by damaging DNA of cells with high replication rates (a key feature of cancerous cells). A chemical marker was also injected to track the chemical’s movement in the body.
It is still too soon to know the results of this study; however, MRI scans confirm that the luminescent chemical marker does indeed cross the BBB. Dr. Michael Canney, the Chief Technology Officer at CarThera, states that he and his team “hope this means the chemotherapy drug is doing the same thing [and that it] will have a significant effect on these tumors.”
The use of microbubbles to treat cancer is only one of the numerous applications researchers have envisioned. Studies on animal models of Alzheimer’s disease (AD) suggests that simply disrupting the BBB can reduce the beta amyloid plaques that are believed to cause AD. Further applications are envisioned for Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis. As these four diseases alone affect more than 20 million patients, the implications of MBs are astounding.