Potent chemotherapy drug reaches brain tumor using new ultrasound technology

A major obstacle in the treatment of glioblastoma, a lethal brain tumor, is the inability of the most intensive chemotherapy to penetrate the blood-brain barrier to reach aggressive brain tumors.

But now, scientists at Northwestern Medicine are using a new skull-implanted ultrasound device to open the blood-brain barrier and repeatedly penetrate a large, critical region of the human brain to deliver chemotherapy in the first human clinical trial. I am reporting the results of the test. Injected intravenously.

A four-minute procedure to open the blood-brain barrier is given while the patient is awake, and the patient is sent home several hours later. The results show that the treatment is safe and well tolerated, with some patients receiving up to 6 cycles of treatment.

This is the first study to successfully quantify the effect of ultrasound-based blood-brain barrier opening on the concentration of chemotherapy in the human brain. Studies have shown that opening the blood-brain barrier increases the concentration of the drug in the human brain by about 4- to 6-fold.

Scientists observed this increase with two different potent chemotherapy drugs, paclitaxel and carboplatin. This drug is not used to treat these patients because it does not cross the blood-brain barrier under normal circumstances.

Moreover, this is the first study to describe how quickly the blood-brain barrier closes after sonication. Scientists have found that most of the blood-brain barrier repair occurs within the first 30-60 minutes after sonication. The findings make it possible to optimize the order of drug delivery and ultrasound activation to maximize drug penetration into the human brain, the authors said.

“This could be a major advance for patients with glioblastoma,” said principal investigator Adam Sonnavent, Ph.D., associate professor of neurosurgery and Northwestern Medical Neurosurgeon at Northwestern University Feinberg School of Medicine. .

Temozolomide, the chemotherapy currently used for glioblastoma, crosses the blood-brain barrier but is a weak drug, Sonnabend said.

The paper was published May 2 in The Lancet Oncology.

The blood-brain barrier is a microscopic structure that protects the brain from most circulating drugs. As a result, the repertoire of drugs available for treating brain disorders is very limited. Patients with brain tumors cannot be treated with most drugs that work for cancers in other parts of the body. This is because these drugs do not cross the blood-brain barrier. Effective repurposing of drugs to treat brain pathologies and cancers requires delivery of drugs to the brain.

In the past, studies injecting paclitaxel directly into the brains of patients with these tumors have observed promising signs of efficacy, but direct injection is associated with toxicities, including brain irritation and meningitis, Sonnabend said. rice field.

The blood-brain barrier closes again after 1 hour

Scientists have found that the opening of the blood-brain barrier using ultrasound and microbubbles is transient, and most blood-brain barrier integrity is restored in humans within an hour after this procedure.

“There is a critical window after sonication when drugs circulating in the bloodstream penetrate the brain,” said Sonnabend, who is also a member of the Northwestern University Robert H. Lurie Comprehensive Cancer Center.

Previous human studies have shown that the blood-brain barrier is fully restored 24 hours after brain ultrasound, and based on several animal studies, the blood-brain barrier is the first in this field. It was supposed to be open for about 6 hours. A Northwestern study suggests that this period may be shorter.

In another first study, using a new skull-implanted grid of nine ultrasound emitters designed by French biotech firm Carthera, a brain nine times larger than the first device (a small single ultrasound emitter) was used. reported that the blood-brain barrier opens to a volume of ultrasound emitter implant). This is important because for this approach to be effective, it must cover a large area of ​​the brain adjacent to the cavity that remains in the brain after removal of the glioblastoma tumor.

A clinical trial in patients with recurrent glioblastoma

The findings form the basis of an ongoing phase II clinical trial that scientists are conducting in patients with recurrent glioblastoma. The purpose of this trial, which uses ultrasound technology to administer a combination of paclitaxel and carboplatin to the brain to participants, is to investigate whether this treatment prolongs survival in these patients. Combinations of these two agents have also been used in other cancers and are the basis for combinations in Phase 2 trials.

In the phase 1 clinical trial reported in this paper, patients underwent surgery for tumor resection and ultrasound machine implantation. They started treatment within weeks after transplantation.

The scientists escalated the dose of paclitaxel, administered every three weeks, accompanied by ultrasound-based opening of the blood-brain barrier. A study was performed during surgery to investigate the effect of this ultrasound device on drug concentrations in a subset of patients. The blood-brain barrier was visualized and mapped using an operating room using a fluorescent dye called fluorescein and MRI obtained after ultrasound therapy.

“Our focus has been on brain tumors (there are about 30,000 gliomas in the United States), and this will open new drug-based treatments for millions of patients suffering from a variety of brain diseases. It opens the door for research,” Sonnabend said.

Other Northwest authors include A. Gould, C. Amidei, R. Ward, KA Schmidt, DY Zhang, C. Gomez, JF Bebawy, BP Liu, IB Helenowski, RV Lukas, K. Dixit, P. Kumthekar , including VA Arrieta. Lesniak, H. Chan, R. Stup.

This research is funded by the National Cancer Institute at the National Institutes of Health, the Lou & Jean Mulnati Brain Tumor Institute at Lurie Cancer Center, and SPORE support from the Mocheri Family Foundation and the Panattoni family.

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