For the first time, doctors have temporarily opened the protective barrier of the human brain and shown that it helps to boost the delivery of cancer medication to brain tumors. The new approach may allow us to temporarily lift the brain barrier. Microbubbles – tiny bubbles of an innocuous gas wrapped in a lipid coating – can be injected into the bloodstream, where they stick around for about 4 minutes. If ultrasound is applied to a specific area of the body or brain within that time, it can cause the bubbles in its path to vibrate. This vibration has been found to temporarily open up the blood-brain barrier in animals, and last year, a team at Sunnybrook Health Sciences Centre in Toronto, Canada, said they had achieved the same feat in one human volunteer.
The ground breaking therapy, which uses tiny bubbles and ultrasound to transport chemotherapy drugs to the brain could also potentially be used to treat Alzheimer’s disease and stroke.
Our brains are protected by a barrier of cells, which act to stop potentially harmful things – from cells to chemical and bacterial toxins – from getting in. But this blood-brain barrier also stops medicines from making their way in, making it difficult for doctors to treat some brain diseases with drugs.
Take glioblastoma, a highly aggressive kind of brain tumor, for example. We have one drug that can bypass the blood-brain barrier to treat the disease. If the tumor becomes resistant to that drug, doctors have to prescribe medicines like carboplatin. With these, only 4 per cent of the dose gets into the brain, says Alexandre Carpentier at the Assisance Publique-Hôpitaux de Paris in France.
The blood-brain barrier (BBB) limits the delivery of systemically administered drugs to the brain. Methods to circumvent the BBB have been developed, but none are used in standard clinical practice. The lack of adoption of existing methods is due to procedural invasiveness, serious adverse effects, and the complications associated with performing such techniques coincident with repeated drug administration, which is customary in chemotherapeutic protocols. Pulsed ultrasound, a method for disrupting the BBB, was shown to effectively increase drug concentrations and to slow tumor growth in preclinical studies. We now report the interim results of an ultrasound dose-escalating phase 1/2a clinical trial using an implantable ultrasound device system, SonoCloud, before treatment with carboplatin in patients with recurrent glioblastoma (GBM). The BBB of each patient was disrupted monthly using pulsed ultrasound in combination with systemically injected microbubbles. Contrast-enhanced magnetic resonance imaging (MRI) indicated that the BBB was disrupted at acoustic pressure levels up to 1.1 megapascals without detectable adverse effects on radiologic (MRI) or clinical examination. Our preliminary findings indicate that repeated opening of the BBB using our pulsed ultrasound system, in combination with systemic microbubble injection, is safe and well tolerated in patients with recurrent GBM and has the potential to optimize chemotherapy delivery in the brain.
A sound attack on brain tumors
Brain tumors are difficult to treat with chemotherapy because the blood-brain barrier greatly limits the delivery of drugs into the brain. Carpentier et al. have developed a pulsed ultrasound device, which they implanted into the skull of patients with glioblastoma, an aggressive and difficult to treat brain tumor, in a first-in-human trial. At regularly scheduled treatment sessions, the researchers activated the ultrasound device by connecting it to a power source, disrupting the blood-brain barrier long enough for subsequent chemotherapy to reach the brain. The authors confirmed that this approach was well tolerated and showed evidence of effectiveness to disrupt the blood-brain barrier, paving the way for further development of this therapeutic approach.
SOURCES – Science Translational Medicine, New Scientist