Ultrasound has been a cancer-diagnosis workhorse for decades, bouncing high-frequency sound waves off of internal tissues and creating echoes that form pictures called sonograms. In the 1990s, researchers began studying the use of ultrasound for tumor ablation, harnessing the ability of sound waves to produce focused heat within the body. Now, they are combining advances in ultrasound technology with nanotechnology in a new category of experimental cancer therapies: microbubbles to facilitate drug delivery.

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"What is promising about focused ultrasound is the potential spectrum of cancer therapies it enables, ranging from hyperthermia to minimally invasive surgery to drug delivery and activation," says Dr. Keyvan Farahani, acting chief of the Image-Guided Intervention Branch in NCI's Cancer Imaging Program, which has helped support this area of research through both academic and small business grants. "These processes can be guided and monitored through a variety of imaging techniques, most notably ultrasound and magnetic resonance imaging," explains Dr. Farahani.

Microbubble-mediated ultrasound therapies are based on ultrasound contrast agents, which were developed to make it easier to differentiate target structure from surrounding tissue during imaging. Ultrasound contrast agents consist of a gas enclosed in a nanoscale lipid coating, called a microbubble, which is about 10 times smaller than the average human vascular cell.

When microbubbles are exposed to doses of ultrasound slightly longer than those used in imaging, the bubbles oscillate in a state called stable cavitation, expanding and contracting and exerting small forces on the tissue around them. With longer exposures, the bubbles collapse (called inertial cavitation), generating high shear stress, temperature, pressure, and shock waves in adjacent cells.

The therapeutic potential of cavitation quickly caught the eye of researchers working on ways to bypass the blood-brain barrier so chemotherapy drugs and other treatments can reach primary and metastatic brain tumors. The blood-brain barrier, a collection of tightly packed epithelial cells within the blood vessels leading to the brain, prevents most larger molecules - including therapeutic drugs - from passing from the bloodstream into the brain.

Researchers had tried to use ultrasound to temporarily open small portions of the blood-brain barrier, but obtained inconsistent results. They realized that microbubbles could be used to concentrate focused ultrasound energy on a precise tissue volume, sparing the surrounding brain tissue from exposure and minimizing damage to healthy cells.

"When we started to use the microbubbles [with ultrasound], we were able to get a reliable window…a blood-brain barrier 'opening' that was large enough to allow drugs through, and could be opened repeatedly," says Dr. Nathan McDannold, research director of the Therapeutic Ultrasound Laboratory at Brigham and Women's Hospital.

Interestingly, it's not clear how microbubble-mediated ultrasound actually causes the blood-brain barrier to open. "We don't think it's just a physical modification of the microvessels - we're not just poking holes in the blood vessels or stretching out the tight junctions," explains Dr. McDannold.

"It's probably related to the stable cavitation of the microbubbles," he continues.

Using electron microscopy, researchers have observed an increase in active transport of drugs across the blood-brain barrier after microbubble-mediated ultrasound, as if in response to physical stimulation from the oscillation.

So far, in animal models, this strategy has successfully delivered chemotherapy and trastuzumab (Herceptin) through small, temporary disruptions in the blood-brain barrier. These disruptions are self-healing, closing most of the way in several hours and completely in less than a week.

In a related area, researchers are looking at the use of inertial cavitation for targeted drug delivery. By loading drugs into the microbubbles or attaching them to their surface, researchers create delivery vehicles that can be injected into the bloodstream and triggered to release their cargo when they are hit by focused ultrasound at precisely the right time and in the correct location.

"Some drugs might have positive effects in one location, and harmful effects in others. If you localize them precisely, you might be able to maximize the dose and avoid the harmful effects," says Dr. Kullervo Hynynen, director of imaging research at Sunnybrook Health Sciences Centre and professor of medical biophysics at the University of Toronto.

An added benefit of this technique, explains Dr. Chrit Moonen, director of the Laboratory for Molecular and Functional Imaging at the Université Victor Segalen Bordeaux 2, is that when the microbubbles collapse and release their payload, the adjacent blood vessels and cell membranes become more permeable from the forces of cavitation, enhancing absorption of the drug.

Before it can be tested in humans, microbubble-mediated ultrasound therapy requires additional safety data. Of particular concern are the consequences of multiple rounds of treatment, whether potential damage to local tissue could be prevented by real-time MRI monitoring, and the effects of high initial concentrations of drugs delivered to a small area of tissue. In vivo studies to address these concerns are currently underway at academic centers around the world.

—Sharon Reynolds

These projects and other ultrasound research were presented at the first annual NIH-sponsored Image-Guided Interventions Workshop, held March 10 and 11 of 2008 in Rockville, Maryland.