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Science to Practice |
Department of Radiology, University of Michigan Hospital, 1500 E Medical Center Dr, University Hospital B1D 502/0030, Ann Arbor, MI 48109-0553
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Within the past decade or so, ultrasound (US) contrast agents have been arousing increased interest. These agents present entirely new possibilities for diagnosis and therapy, and they have the potential to expand the uses of contrast agents far beyond mere image enhancement. In this issue of Radiology, Takeuchi et al (1) report their investigation of the intracellular stability of two contrast agents.
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Initially, US contrast agents were air-filled microbubbles that were relatively unstable. They soon evolved, however, into agents that contained perfluorocarbon gases—large molecules that are highly insoluble in blood, making them long lived compared with their air-filled predecessors. These materials have now developed into third-generation targeted agents, with even more sophisticated properties such as shells of different chemical design. Accompanying these chemical advances, there are now changes in US transmission pulse sequences that take advantage of the fact that gas-containing contrast agents are compressible and because of this will respond in a nonlinear fashion to different input sound fields. Just as in magnetic resonance (MR) imaging, where one tries to "catch" precessing protons during different phases of rotation by varying local magnetic fields to generate contrast, US can now cause microbubbles to oscillate differently on the basis of the characteristics of the US field. The analogy with MR imaging is remarkably close, and, as with MR imaging, we are already seeing rapid and dramatic developments in US transmission and reception pulse sequences. Further, these microbubble contrast agents have already proved to be tremendously flexible and robust. For example, (a) ligands attached to microbubble shells allow binding to different targets (2); (b) DNA/genes embedded in shells can be transfected into cells by using external US energy (2,3); and (c) cavitation and microbubble disruption and expansion produced by external US fields hold substantial potential for noninvasive focal therapies of tumors, vascular malformations, and dissolution of thrombi (2–4).
In the study by Takeuchi et al (1), the agents used were phagocytosed by leukocytes, potentially making it possible to image inflammation directly. One agent, BR14 (Bracco Research, Geneva, Switzerland), has a phospholipid shell, and the other, Optison (Tyco Health Care, Mallinckrodt, St Louis, Mo), has an albumin shell. Ostensibly, and primarily because of this difference, BR14 was inherently more stable and could withstand higher intensity external fields better than could Optison. In fact, Takeuchi et al showed that these microbubbles respond differently to externally applied US fields and that this response can be modulated by the strength of the external field. In other words, the authors were able to control and modify an externally administered intracellular marker by using an external US source.
Takeuchi et al (1) were able to demonstrate the intracellular stability difference by using electron microscopy, intravital microscopy, and biochemical parameters that depict apoptosis and cell wall disruption independently. The effect of the stability difference between these agents would presumably be advantageous when imaging inflammation secondary to a myocardial infarction, where one would like to limit any augmentation of the inflammatory response that might be induced by possible cell wall disruption caused by rupturing intracellular contrast agent microbubbles. In addition, a more stable agent would permit imaging for longer times, assuming the microbubble response to the US field is adequate. For both of these reasons, the more stable agent would be desirable.
The Practice
Clinical use.—In the United States, practice is presently limited because the Food and Drug Administration has resisted approving US contrast agents for general use. In the rest of the world, however, the prospects for the use of these agents are virtually limitless. Investigators have already demonstrated dramatic images of tumor blood flow and myocardial wall perfusion by using nontargeted agents and pulse sequences such as pulse inversion or pulse-inversion Doppler that are tailored to contrast agents (5,6). Advanced agents targeted to specific cell types and functions, such as those demonstrated by Takeuchi et al, will only make these results even more dramatic.
Future opportunities and challenges.—The results of Takeuchi et al (1) have more potential for future applications than for current use. The authors do not show images in their article. However, the potential and consequences of work like theirs are considerable. Even at this early stage, US contrast agents can be tailored and optimized for specific functions. These agents will only become more sophisticated with time.
Summary
Takeuchi et al (1) have shown how changes in composition of the walls of microbubble contrast agents can alter the responses of microbubbles to external US fields. The microbubbles investigated in their study were evaluated for potential use in imaging of inflammation. Future modifications in microbubble shell design should permit broader and more sophisticated applications in diagnosis and therapy.
FOOTNOTES
See also the article by Takeuchi et al in this issue.
REFERENCES
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