Double-walled ultrasound agent takes long ride in bloodstream

Therapy potential could expand ultrasound’s reach

Does ultrasound ring a bell? In a way, it does. This versatile imaging modality could be ringing—and even shattering—a multitude of tiny bells within the body once a new generation of ultrasound contrast technology is certified for use by the Food and Drug Administration. Ultrasound’s utility and the breadth of its clinical applications could be increased significantly in the process. Scanners might even one day be aimed at ultrasound-activated drug therapy applications similar in broad concept to light-activated photodynamic drug therapy.

These bells are really air-filled, double-walled microspheres, dubbed biSpheres, under development by Point Biomedical of San Carlos, CA. Like bells, biSpheres can be manufactured to ring at different pitches—or, rather, reflect ultrasound waves optimally at different frequencies. Furthermore, when the power and frequency of the ultrasound scanner are adjusted differently, biSpheres can be made to break, releasing therapeutic or imaging agents to a localized area in the patient.

Point’s biSpheres are part of a third generation of ultrasound contrast agents now under development, according to Ron Yamamoto, president and CEO of Point Biomedical. As ultrasound contrast technology progresses, it will last longer in the body and will improve signal-to-noise performance. Another company developing third-generation ultrasound contrast is Acusphere of Cambridge, MA (SCAN 6/15/94 and 11/25/98).

First generation agents, like Molecular Biosystems’ Albunex albumin microspheres, might last for about a minute when illuminating the endocardium within the ventricles of the heart, Yamamoto said. Second-generation technology, such as Sonus Pharmaceuticals’ EchoGen fluorocarbon gas contrast, provides four or five minutes of continuous imaging in this application. The next ultrasound contrast generation should extend this imaging time to 20 to 30 minutes, or about the time of a cardiac ultrasound examination.

“This might be the first truly usable contrast agent,” Yamamoto said. “The first generation was more of a demonstration of feasibility. The second generation showed the promise of clinical utility, but, with short persistence and suboptimal acoustic results, it still has not seen widespread use.”

Point’s biSphere technology is in phase I clinical trials for use in studying myocardial perfusion. Initial results were presented last week at the American Society of Echocardiography meeting in Washington, DC. Yamamoto spoke with SCAN shortly before the meeting.

Point anticipates FDA certification by the end of 2001 and product launch in 2002, he said. The company is talking with several potential partners to assist in marketing and distribution of biSphere contrast in the U.S., Europe, and Japan.

Potential in radiology. Following certification of biSphere contrast as a cardiac agent, Point will seek expansion of indications to radiology applications, including blood-pool imaging and imaging of the lymphatic system, Yamamoto said. Further down the road, the company will apply for therapeutic indications of the agent, with a focus on high-end applications not currently feasible, such as treating severely damaged hearts and inoperable tumors.

About 14 million echocardiography procedures are performed every year in the U.S. Overall, the worldwide market potential for ultrasound contrast in cardiology and radiology applications has been estimated at $500 million to $1 billion annually, Yamomoto said.

The key to Point’s technology is found in the double walls of the biSpheres, he said. The outer wall is built with a soft hydrogel material composed of human albumin. This material provides a gentle interface with the blood, which does not respond well to foreign material. The inner wall, on the other hand, is made of a strong polymer material, which can resist normally severe pressures within the heart.

“What we get is a gentle circulation and a long circulation time from a single injection for diagnostic purposes,” Yamomoto said.

This encapsulation technology enables Point to use air within the biSphere, which has acoustic properties superior to fluorocarbon gas, he said. The second-generation agents are not able to provide a sealed shell and so have to work with a gas that is not quickly absorbed into the blood. For simplicity’s sake, Point is using pure nitrogen, which is acoustically comparable to air, within the biSpheres in the FDA trials.

Point can acoustically tune the biSphere using the mechanical properties of its inner wall, Yamamoto said. Just as two bells of equal size will ring at different pitches if their thicknesses vary, the inner wall can be constructed for optimal function at different ultrasound frequencies. These could range from 4 MHz for deep penetration in cardiac imaging to 8 MHz for imaging fine structures at shallower depths in radiology applications.

“We change the wall thickness and can tune for the right frequency,” Yamamoto said. “This gives us good acoustic signal response.”

If clinical trials pan out, Point’s technology holds the potential for real-time ultrasound myocardial perfusion examinations, which would provide a much quicker—and cheaper—diagnosis of heart attacks than the nuclear medicine procedures currently in use, Yamamoto said. When a patient comes to an emergency room, a more rapid diagnosis may either speed therapy or rule out a heart attack, allowing the patient to go home and avoid expensive hospitalization.

Ultrasound is not the only imaging modality relevant to biSphere technology. Point is also investigating the encapsulation of MRI agents, using biSphere contrast as an MRI blood-pool agent, he said.

“Right now, everybody is interested in (MR angiography),” Yamamoto noted.

© 1999 Miller Freeman, Inc.All rights reserved.

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