Breakthrough Procedure Enables Chemotherapy To Enter the Brain

A first-in-human clinical trial has successfully delivered chemotherapy drugs through the blood–brain barrier using ultrasound, with the potential to aid treatment for the deadly brain cancer glioblastoma. The research is published in The Lancet Oncology.

Circumventing the blood–brain barrier

The blood–brain barrier is a physical barrier that helps to protect the brain. It is formed of blood vessels and tightly spaced cells that create a semi-permeable barrier, controlling the molecules that can enter the brain from the blood and helping to prevent harmful substances and pathogens from reaching the central nervous system.

However, the blood–brain barrier also prevents the vast majority of circulating drugs from reaching the brain, making the treatment of brain cancers and other brain diseases especially difficult. Most drugs that are effective for other cancers fail to treat brain cancer as they cannot cross the blood–brain barrier.

Previously, efforts to repurpose chemotherapy drugs for brain cancers required delivery directly into the brain. For example, direct injection of the chemotherapy drug paclitaxel into the brain has shown some promising efficacy, though it comes at the cost of adverse effects such as brain irritation and meningitis.

In the current study, the researchers used ultrasound devices implanted into patients’ skulls to temporarily open the blood–brain barrier and administer intravenous chemotherapy to the brain in an effort to improve glioblastoma treatment.

Chemotherapy successfully reaches the brain

Implantable ultrasound devices were inserted into patients’ skulls during surgery to remove their tumor in this first-in-human Phase 1 clinical trial.

The devices produce microbubbles that open the blood–brain barrier during a four-minute procedure while the patients are awake, and patients can begin their treatment within just a few weeks of their surgery.

The participants were treated with intravenous chemotherapy drugs paclitaxel and cisplatin – which are not normally used for glioblastoma due to their inability to cross the blood–brain barrier – along with the barrier-opening procedure.

The treatment was generally well-tolerated by the patients and could be repeated safely, with some patients undergoing up to six treatment cycles. A number of patients were treated during surgery to measure drug concentrations in the brain, revealing that drug concentration in these patients increased by approximately four- to six-fold.

“This is potentially a huge advance for glioblastoma patients,” said Dr. Adam Sonabend, lead author of the study, neurosurgeon and associate professor of neurological surgery at Northwestern University Feinberg School of Medicine. Sonabend also noted that temozolomide, the current drug of choice for glioblastoma, does cross the blood–brain barrier but is a relatively weak drug.

The researchers also discovered that the majority of the blood–brain barrier closes again within the first 30–60 minutes following the ultrasound procedure, much shorter than the 6-hour window suggested by previous animal studies. “There is a critical time window after sonification when the brain is permeable to drugs circulating in the bloodstream,” Sonabend said. These findings may help optimize the drug delivery sequence and maximize the amount of drug reaching the brain in future studies.

Improving patient survival?

“While we have focused on brain cancer (for which there are approximately 30,000 gliomas in the US), this opens the door to investigate novel drug-based treatments for millions of patients who suffer from various brain diseases,” Sonabend said.

The researchers are now building upon these findings in a Phase 2 clinical trial in patients with recurrent glioblastoma. This will assess whether delivery of chemotherapy drugs paclitaxel and carboplatin to the brain using this ultrasound technique may improve patient survival.

Reference: Sonabend AM, Gould A, Amidei C, et al. Repeated blood–brain barrier opening with an implantable ultrasound device for delivery of albumin-bound paclitaxel in patients with recurrent glioblastoma: a phase 1 trial. Lancet Oncol. 2023;24(5):509-522. doi: 10.1016/S1470-2045(23)00112-2

This article is a rework of a press release issued by Northwestern University. Material has been edited for length and content.