Implantable ultrasound device opens blood-brain barrier to deliver chemotherapy for glioblastoma treatment

Northwestern Medicine researchers have made a breakthrough in treating glioblastoma, a deadly brain cancer, by using a novel skull-implantable ultrasound device. The main obstacle to treating this aggressive brain tumor has been the inability of potent chemotherapy to penetrate the blood-brain barrier.

In the first-ever clinical trial, scientists successfully opened the blood-brain barrier and delivered chemotherapy directly to the tumor site in critical areas of the human brain. Patients undergo a brief four-minute procedure while awake, and are able to go home after just a few hours. The treatment has been proven safe and effective, with some patients receiving up to six cycles of treatment.

This study is groundbreaking in that it is the first to measure the effect of ultrasound-based blood-brain barrier opening on drug concentrations in the human brain. The results indicate a four- to six-fold increase in drug concentration in the brain, which is a significant development in the treatment of glioblastoma.

The study revealed that two potent chemotherapy drugs, paclitaxel and carboplatin, which normally cannot cross the blood-brain barrier, showed an increase in drug concentration in the brain after ultrasound-based blood-brain barrier opening. This breakthrough offers new hope for treating patients with glioblastoma.

Furthermore, the research team was able to determine that the blood-brain barrier closes rapidly after sonication, with most restoration occurring within the first hour. This information can help optimize drug delivery and ultrasound activation for maximum effectiveness in penetrating the brain.

Dr. Adam Sonabend, lead investigator and neurosurgeon at Northwestern Medicine, expressed excitement about the potential impact on glioblastoma patients, stating that the current chemotherapy drug used, Temozolomide, is weak and this discovery offers a significant advance in treatment options.

The paper will be published May 2 in The Lancet Oncology.

The blood-brain barrier serves as a protective barrier that restricts the entry of the vast majority of drugs into the brain. This limitation severely restricts the range of drugs that can be used to treat brain-related diseases, including brain cancer. Standard cancer treatments that work elsewhere in the body are typically ineffective due to the blood-brain barrier’s hindrance to drug delivery. Effective drug repurposing to treat brain diseases and cancer requires a means to deliver drugs to the brain.

Previous studies have demonstrated that direct injection of paclitaxel into the brains of patients with these tumors showed potential efficacy. However, this approach was associated with toxic side effects such as brain irritation and meningitis, according to Dr. Sonabend.

Blood-brain barrier recloses after an hour

The study found that the use of ultrasound and microbubble-based blood-brain barrier opening is temporary, and most of the barrier’s integrity is restored within an hour after the procedure is performed in humans. This discovery has revealed a critical time window after sonication when the brain becomes permeable to drugs circulating in the bloodstream, according to Dr. Sonabend.

Previous studies on humans had shown that the blood-brain barrier is fully restored within 24 hours after brain sonication. Animal studies suggested that the barrier is open for the first six hours. However, the Northwestern study indicates that this time window may be even shorter.

Additionally, the study reports a significant breakthrough in the form of a novel skull-implantable grid of nine ultrasound emitters designed by French biotech company Carthera. This grid can open the blood-brain barrier in a larger volume of the brain, approximately nine times more than the initial small single-ultrasound emitter implant. This is crucial as the treatment requires coverage of a large region of the brain surrounding the cavity left behind after glioblastoma tumor removal to be effective.

Clinical trial for patients with recurrent glioblastoma

The results of this study have led to an ongoing phase 2 clinical trial for patients with recurrent glioblastoma, in which they receive a combination of paclitaxel and carboplatin delivered to their brain using the ultrasound technique to investigate whether the treatment prolongs survival. In the phase 1 trial, patients underwent surgery to remove their tumors and had the ultrasound device implanted. The dose of paclitaxel was escalated every three weeks, and the ultrasound-based blood-brain barrier opening was performed in conjunction with the chemotherapy. The ultrasound device’s effect on drug concentrations was investigated in subsets of patients during surgery by visualizing and mapping the blood-brain barrier using fluorescein and MRI. This research could lead to the development of novel drug-based treatments for millions of patients who suffer from various brain diseases, not just brain cancer.

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