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Running the Numbers
Researchers Verify Theory Behind Ultrasound Drug Delivery
FDA Approved: Integrated IVUS Technology Given Nod from FDA

Researchers Verify Theory Behind Ultrasound Drug Delivery

By Renee DiIulio

One of the hallmark advantages of ultrasound is the possibility to noninvasively target an area for drug delivery, much as it can be used to noninvasively image the body,” says Mark Prausnitz, PhD, professor of chemical and biomedical engineering at the Georgia Institute of Technology (Atlanta). Prausnitz is one of the authors of a study published in the journal of Ultrasound in Medicine and Biology,¹ which verified the hypothesized mechanism by which ultrasound delivers drugs into a cell.

The scanning electron micrograph (left) shows a prostate-cancer cell immediately after exposure to ultrasound. The transmission electron micrograph (right) shows a prostrate-cancer cell after ultrasound has been used to break the membrane. The images have been color enhanced to show the spot where the cell membrane has been removed.

To date, there had not been a study that examined the leading theory that the method worked by putting a hole in cells, according to Prausnitz. So, the Georgia Tech researchers, collaborating with Emory University (Atlanta), decided to resolve the mystery. Using five different microscopy techniques, they determined that the ultrasound mechanism works by increasing the cavitation bubble activity to the point of collapse, Prausnitz explains.

The resulting effect creates holes in the tissue cells through which therapeutic molecules, as large as 50 nm in size, are able to enter. The cell then repairs the hole using its own systems.

“The overall goal for the research community is to use ultrasound to drive drugs selectively into a general tissue so that the drug has a greater effect,” Prausnitz says. The drug, which could include small proteins or DNA, could be injected locally or throughout the body with targeted ultrasound to enhance uptake.

Potential areas of benefit include oncology, gene therapy, and even cardiovascular treatment. Prausnitz provides an example: “If you can get a chemotherapeutic to act preferentially at the site exposed to the ultrasound, you can get more effect where you want it. So, you can reduce the whole-body dose of the drug and get fewer side effects.”

The possibilities of side effects with ultrasound as a drug deliverer exist, but animal studies have not documented any significant permanent damage as a result of the therapy. “The resulting hole could be large enough or stressful enough to cause the cell to die, in the extreme case, or to reseal itself but maintain imbalances for some period of time that affect the cell, in the less extreme,” Prausnitz says.

Georgia Tech researchers Mark Prausnitz, PhD, and Robyn Schlicher use a confocal microscope to study cells whose membranes have been opened by the application of ultrasound.

The ultrasound conditions used to open the cells require power levels and frequencies higher than those used in either diagnostic or therapeutic ultrasound methods today. “We add both a thermal component and a mechanical component, which has to do with the bubble activity,” he says, noting that diagnostic instruments in the United States are designed to eliminate the effects of bubble activity. “But we are trying to harness those effects.” Widespread use could mean different instrumentation down the road. “The medical community might be able to adapt existing equipment, but it is more likely that we will want to design equipment that can achieve the desired results in a controlled way,” he says.

Before manufacturers develop new systems, however, the technique will require more research. Prausnitz suggests the need to both identify the most compelling diseases and drugs that ultrasound can impact and to determine the most appropriate conditions to use, including bubbles. “Should we add agents, and if so, what type? Are there other components, such as chemicals, that need to be added to the system to facilitate drug delivery or help the cells repair themselves?” asks Prausnitz. Additional studies will need to address human efficacy and safety.

Fortunately, research is under way. “A community of researchers at universities and companies is looking at ultrasound for drug delivery,” he says. “The field has grown over the past 10 years.”

Renee DiIulio is a contributing writer for Medical Imaging. For more information, contact .

Reference

1. Schlicher RK, Radhakrishna H, Tolentino TP, Apkarian RP, Zarnitsyn V, Prausnitz MR. Mechanism of intracellular delivery by acoustic cavitation. Ultrasound Biol Med. 2006;32:915?924. Available at: dx.doi.org/10.1016/j.ultrasmedbio.2006.02.1416. Accessed October 9, 2006.

FDA Approved: Integrated IVUS Technology Given Nod from FDA

The FDA recently granted 510(k) market clearance to GE Healthcare (Waukesha, Wis) and Volcano Corp (Rancho Cordova, Calif) for the integration of Volcano’s intravascular ultrasound (IVUS) imaging capabilities into GE Healthcare’s Innova all-digital x-ray cath lab imaging system. The new product is the result of a March 2006 agreement between the two companies and will be marketed under the name Innova IVUS.

Shown here is an Innova IVUS exam, through which physicians can look at the patient?s arteries.

The integrated product is made possible by Volcano’s PC-based IVUS platform, which boasts reduced console size, weight, and noise; thus, the unit can be located in the control room. The Innova platform contributes its Innova Central touch-screen system, and the integrated interface optimizes IVUS workflow.

With integrated IVUS, physicians will have easier access to imaging tools that can aid in both diagnosis and therapeutic procedures, such as stent placement and assessment. The technology also can help determine the lesion length and the optimal stent length and diameter. Further-more, users have the option of additional control devices, including a trackball and joystick.

The IVUS patient interface module can be hung on the bed rail, and the central processing unit is placed outside the main flow of traffic in the cath lab. Patient information automatically transfers from Innova to the IVUS, and physicians can view images on the existing monitor bank, a separate IVUS monitor, or a monitor in the control room. Innova IVUS also integrates with the cath lab’s archiving system, storing its cases as substudies to the cath lab study.

“When you have a catheterized patient on the table, you need your diagnostic and therapeutic tools to be ready for quick and simple implementation,” Mark Wholey, MD, chairman of the Pitts-burgh Vascular Institute at the University of Pennsylvania Medical Center, said in a press release. “We have been asking for this advance from the IVUS companies for some time now.”

The integrated system currently is available for sale from GE Healthcare, and it will be co-marketed by both GE Healthcare and Volcano.

—C. Vasko