Opening up the blood-brain barrier to deliver drugs (credit: Focused Ultrasound Foundation)
The blood-brain barrier has been non-invasively opened in a human patient for the first time. A team at Sunnybrook Health Sciences Centre in Toronto used focused ultrasound to temporarily open the blood-brain barrier (BBB), allowing for effective delivery of chemotherapy into a patient’s malignant brain tumor.
The team infused the chemotherapy agent doxorubicin, along with tiny gas-filled bubbles, into the bloodstream of a patient with a brain tumor. They then applied focused ultrasound to areas in the tumor and surrounding brain, causing the bubbles to vibrate, loosening the tight junctions of the cells comprising the BBB, and allowing high concentrations of the chemotherapy to enter targeted tissues.
This patient treatment is part of a pilot study of up to 10 patients to establish the feasibility, safety, and preliminary efficacy of focused ultrasound to temporarily open the blood-brain barrier to deliver chemotherapy to brain tumors. The Focused Ultrasound Foundation is currently funding this trial through their Cornelia Flagg Keller Memorial Fund for Brain Research. Based on these two pre-clinical studies, a pilot clinical trial using focused ultrasound to treat Alzheimer’s is being organized.
Dr. Kullervo Hynynen, senior scientist at the Sunnybrook Research Institute, has been performing similar pre-clinical studies for about a decade. In 2012, his team was able to bypass the BBB of a rat model non-invasively (see Bypassing the blood-brain barrier with MRI and ultrasound).
Previous methods where invasive, requiring an operation, such as an implanted mucosal graft in the nose (see A drug-delivery technique to bypass the blood-brain barrier and Researchers bypass the blood-brain barrier, widening treatment options for neurodegenerative and central nervous system disease) or inserting needle electrodes into the diseased tissue and applying multiple bursts of pulsed electric energy (see Blood-brain-barrier disruption with high-frequency pulsed electric fields).
Fighting disease
The researchers suggest that focused ultrasound could also be used to deliver other types of drugs, DNA-loaded nanoparticles, viral vectors, and antibodies to the brain to treat a range of neurological conditions, including various types of brain tumors, Parkinson’s, Alzheimer’s and some psychiatric diseases.
For example, the temporary opening of the blood-brain barrier appears to facilitate the brain’s clearance of a key pathologic protein related to Alzheimer’s and improves cognitive function, the researchers found. And a recent study at the Queensland Brain Institute in Australia demonstrated that opening the blood-brain barrier with focused ultrasound reduced brain plaques and improved memory in a mouse model of Alzheimer’s disease.
Focused Ultrasound Foundation
Abstract of Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer’s disease mouse model
Transgenic mice with increased amyloid-β (Aβ) production show several aspects of Alzheimer’s disease, including Aβ deposition and memory impairment. By repeatedly treating these Aβ-forming mice with scanning ultrasound, Leinenga and Götz now demonstrate that Aβ is removed and memory is restored as revealed by improvement in three memory tasks. These improvements were achieved without the use of any therapeutic agent, and the scanning ultrasound treatment did not induce any apparent damage to the mouse brain. The authors then showed that scanning ultrasound activated resident microglial cells that took up Aβ into their lysosomes. These findings suggest that repeated scanning ultrasound may be a noninvasive method with potential for treating Alzheimer’s disease.