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MRI-guided ultrasound delivers drug to brain

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David Shenkenberg

The blood-brain barrier prevents harmful substances from entering the brain, but it also obstructs the passage of beneficial drugs, necessitating invasive procedures to deliver them. The breast cancer drug Herceptin — and other antibody-based drugs — cannot cross the barrier, but now researchers have attempted to deliver it across the blood-brain barrier of mice using a focused ultrasound transducer, while guiding the transducer and monitoring the results with MRI.

Kullervo Hynynen’s group at Brigham and Women’s Hospital and at Harvard Medical School, both in Boston, were the authors of the study. They chose Herceptin because of its effectiveness in treating metastatic breast cancer. However, it cannot reach tumors that metastasize to the brain unless doctors use invasive methods to deliver it. As they demonstrated in a previous paper, ultrasonic waves create minute, temporary openings in the blood-brain barrier when used at an appropriately low pressure.

The scientists built their own ultrasound transducer, which, unlike diagnostic ultrasound, was focused and used a longer 10-ms burst of ultrasonic waves. They operated the transducer at 0.69 MHz because low frequencies are ideal for focusing through the skull and disrupting the barrier.

They used a GE Healthcare MRI scanner to focus the ultrasound and to measure the amount of drug delivered. They chose the imaging method because it has good soft tissue contrast and spatial resolution. They aimed the ultrasound at the brain while using a gradient-echo MRI sequence, and they observed the brain using the T1-weighted fast-spin echo method. The concentration of the MRI contrast agent is proportional to the signal intensity of the T1-weighted sequences, whereas gradient echo is fast and can detect temperature elevations. They assessed tissue damage resulting from the ultrasound by histological examination of the mouse brains.

The researchers opened the barrier at a minimum pressure of 0.6 MPa and did not detect tissue hemorrhage at this pressure. At 0.8 MPa, blood cells leaked in small, scattered areas.

In eight of nine of the control mice, the amount of Herceptin that entered the brain was below the limit of detection. However, 1032 ng/g of tissue entered the brain in one of the control mice because of experimental uncertainty and biological variation. Using ultrasound at 0.6 MPa and 0.8 MPa, 1504 and 3257 ng of the drug per gram of tissue entered the brain, respectively.

The researchers believe that they can translate this method to human treatment. They previously evinced that a focused array can safely disrupt the barrier in humans, and they believe that they can use this technique to deliver other antibodies to the brain, such as those against b-amyloid, which some evidence suggests may cure Alzheimer’s disease.

PNAS, Aug. 1, 2006, pp. 11719-11723.

Sep 2006

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