First Time Cancer Chemotherapy Drug Can Enter the Human Brain

A new ultrasonic device has shown promise in human testing, with results suggesting it may temporarily break the blood-brain barrier and administer chemotherapy straight to the brain. The novel ultrasound technology shows promise in the battle against glioblastoma, for which there is currently no useful therapy.

The cancer known as glioblastoma originates in cells called astrocytes, which are normally responsible for offering assistance to nerve cells. Glioblastoma is a kind of cancer that may affect both the brain and the spinal cord. It can express itself in either site as an abnormal growth of cells. It also has the potential to infiltrate good tissue and destroy it, in addition to having a high growth rate.

No age range is immune to the risk of developing glioblastoma. On the other hand, older people and men are more likely to be impacted by this illness than younger adults. This is especially true in the United States. Headaches that keep getting worse, nausea and vomiting, double vision or impaired eyesight, seizures, and blurred or double vision are some of the symptoms of glioblastoma.

The inability of the most powerful chemotherapy medications to cross the blood-brain barrier and reach the rapidly expanding brain tumor is one of the most difficult aspects of treating glioblastoma, a form of brain cancer that almost always results in death.

In an article published by The Lancet Oncology, Northwestern Medicine researchers have just recently revealed the findings of the first human clinical study in which they deployed a novel ultrasonic device that may be implanted inside of a human skull. This device breaks through the blood-brain barrier, which makes it possible for repeated penetration of broad portions of the brain. As a result, it makes it possible to administer chemotherapy by intravenous injection.

A patient is allowed to remain conscious throughout the blood-brain barrier opening operation, which lasts about four minutes and then will enable them to return home a few hours later. The findings suggest that the therapy is risk-free and well-tolerated by patients; some patients underwent as many as six treatment cycles.

This is the first research that has effectively quantified the impact of breaching the blood-brain barrier using ultrasound on the levels of chemotherapy found in the human brain. The findings demonstrated that when the blood-brain barrier was broken, there was an estimated four- to six-fold increase in the concentration of drugs found in human brain tissue.

Paclitaxel and carboplatin are very effective chemotherapy medicines, and researchers found that both contributed to this rise. These individuals are not treated with pharmaceuticals because, under normal conditions, the drugs do not pass the barrier that separates the blood and the brain.

In addition, this is the first research to demonstrate how soon the blood-brain barrier re-establishes itself following sonication. According to the findings of the experts, the majority of the repair of the blood-brain barrier occurs in the first thirty to sixty minutes following sonication. According to the study's authors, the results will make it possible to optimize the sequence of drug administration and ultrasonic activation to enhance the penetration of the medication into the human brain.

According to the primary investigator, Dr. Adam Sonabend, who is also an associate professor of neurological surgery at Northwestern University Feinberg School of Medicine and a neurosurgeon at Northwestern Medicine, "This has the potential to be a very significant advance for glioblastoma patients."

According to Sonabend, the chemotherapeutic medication temozolomide, which is currently used to treat glioblastoma, can pass the blood-brain barrier but is an ineffective medicine.

A small structure known as the blood-brain barrier protects the brain from the overwhelming majority of medications circulating in the body. As a direct consequence of this, the selection of available medications for treating brain illnesses is quite restricted. Because these treatments do not pass across the blood-brain barrier, it is not possible to treat patients with cancer in the brain with the majority of the drugs that are ordinarily useful for treating cancer in other parts of the body. The administration of the medicine in question is necessary for its successful repurposing in treating brain disease and cancer.

According to Sonabend, in the past, researchers have noticed encouraging indicators of success in tests in which they injected paclitaxel directly into the brains of patients with these tumors. However, the direct injection was linked with complications such as brain inflammation and meningitis.

The researchers concluded that the opening of the blood-brain barrier that is caused by the use of ultrasound and microbubbles is only temporary and that the majority of the blood-brain barrier's integrity is restored within an hour of having this operation performed on people.

"There is a critical time window after sonification when the brain is permeable to drugs circulating in the bloodstream," Sonabend said. "It is important to take advantage of this time window."

Previous human research has shown that the blood-brain barrier is entirely repaired 24 hours after brain sonication. However, based on the findings of several animal studies, the field has hypothesized that the blood-brain barrier remains open for about the first six hours following brain sonication. According to the results of the Northwestern research, this window of opportunity may be shorter.

Another first to come out of this research is the discovery that by employing a unique grid of nine ultrasonic emitters that can be implanted in the skull and was built by the French biotech firm Carthera, the blood-brain barrier can be opened in a volume of the brain that is nine times greater than the first device, which was a tiny implant that had a single ultrasound emitter. This is significant because for this strategy to be successful, it needs coverage of a broad section of the brain next to the hollow left in the brain after glioblastoma tumors have been removed.

Results

The research results are being used as the foundation for a clinical trial now in phase 2 and are conducted by scientists for individuals who have had glioblastoma return. The participants in the study will get a combination of paclitaxel and carboplatin, which will be administered to their brains via the ultrasonic method. The experiment aims to determine whether or not this therapy extends the amount of time that these patients can survive. The fact that these two medications have previously been used together in the treatment of other types of cancer provides the rationale for combining them in the phase 2 study.

Patients who participated in phase 1 clinical study described in this publication had their tumors surgically removed and an ultrasound device implanted in their bodies simultaneously. They began therapy just a few short weeks after the implantation had taken place.

Studies were conducted during surgery on subgroups of patients to explore the impact of this ultrasonic device on the medication concentrations in their systems. The researchers increased the amount of paclitaxel administered every three weeks, along with the opening of the blood-brain barrier caused by ultrasound. In the operating room, the blood-brain barrier was observed and mapped using a fluorescent dye known as fluorescein and an MRI that was acquired following ultrasonic treatment.

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                                   Repeated blood–brain barrier opening with an implantable ultrasound device