摘要：Penetrating the blood-brain barrier via pulses of ultrasound waves led to a three-fold increase in the concentration of a chemotherapy drug in people with the brain cancer glioblastoma multiforme
Ultrasound waves help to open up the blood-brain barrier, which could allow for more-targeted treatment of hard-to-reach brain tumours.
The blood-brain barrier (BBB) is made up of many cell types that help to shield the brain from toxic substances and microorganisms that may be circulating in the bloodstream. However, this roadblock can also prevent cancer drugs from reaching malignant cells in the brain.
Now, Adam Sonabend at Northwestern University, Illinois, and his colleagues have used low-intensity pulsed ultrasound to open the BBB of 17 people with recurrent glioblastoma multiforme (GBM), an aggressive brain tumour. Existing treatments focus on removing as much of the tumour as possible, followed by radiotherapy and use of the chemotherapy drug temozolomide, which can cross the BBB, but is weaker than some other anti-cancer drugs.
The participants underwent a craniotomy, an operation to open the head to expose the brain, which enabled doctors to partly remove their tumours. During this surgery, a SonoCloud-9 device, which emits ultrasound waves, was fitted into a cutout region of their skulls.
Some of the participants received the chemotherapy drug paclitaxel during this surgery and its concentration was measured in their brains.
Between one and three weeks later, all of the participants’ ultrasound devices were activated. During this activation, microbubbles were administered into the participants’ brains. The bubbles moved in response to the ultrasound waves, creating a mechanical stress that helped to open the BBB.
The procedure took 4 minutes and the participants remained awake throughout. Paclitaxel was then given intravenously at an increasing dose every three weeks for up to six cycles.
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After the intervention, the average concentration of paclitaxel in the brain was 3.7 times higher than when the drug was administered without the ultrasound devices being active earlier in the experiment. It is unclear whether this improves survival among people with recurrent GBM, but a higher drug concentration in the brain suggests more effective treatment outcomes, say the researchers.
The BBB closed within 1 hour, enabling it to perform its regular functions, they say.
The repeated opening and closing of the barrier over the intervention’s numerous cycles didn’t cause any severe side effects, says Sonabend. Headache was the most commonly reported adverse event, affecting 71 per cent of the participants. Some also reported pins and needles, facial or limb weakness and blurred vision, all of which were temporary.
The study shows that this procedure is feasible and safe in people, says Michael Lim at Stanford University, California. “A small, implantable device that can open up the BBB in outpatient clinic can be very helpful for glioblastoma patients.”
The BBB can already be opened with some medications, but this procedure could open a larger section, allowing more of a cancer drug to penetrate, says Lim.
The researchers are now testing the approach in more people with GBM when paclitaxel is administered alongside the chemotherapy drug carboplatin, which are commonly given together, says Sonabend.
Journal reference: The Lancet OncologyDOI: doi.org/10.1016/S1470-2045(23)00112-2