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Science to Practice |
1 Imaging Sciences Department, Faculty of Medicine, Imperial College, Hammersmith Hospital Campus, Du Cane Rd, London, W12 0HS, England m.blomley@imperial.ac.uk
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Given the advantages of ultrasonography (US), including its flexibility, wide availability, and therapeutic potential, it is surprising that it has received comparatively little attention as a molecular imaging tool. In this issue of Radiology, Hauff and colleagues provide (at the time of this writing) the first published article on a lymph node–specific microbubble (1). They made an agent with a highly specific acoustic signature that allows its localization to be easily mapped in vivo, by incorporating an antibody that targets the L-selectin ligand, which is expressed in lymph node venules.
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In addition to enhancing the blood pool after injection, some microbubbles are known to target tissues such as the liver, spleen, or activated endothelium. The mechanisms of this "passive" targeting are poorly understood but probably relate to properties of the shell material. Active targeting strategies can be used in which antibodies or peptides are attached to microbubble shells. With use of such methods, in vivo targeting of activated platelets, neovessels in tumors, and endothelium has been described (2). There is currently no method of targeting lymph nodes with intravenous microbubbles; although when microbubbles are injected directly into tissues, they may be taken up by the lymph nodes directly. This method has been advocated for sentinel node imaging (3).
Most current microbubble imaging methods rely on application of US at low powers and detection of harmonic emissions. The most sensitive method of imaging microbubbles, however, is to use higher-power US to deliberately disrupt microbubbles, which produces a very strong and highly characteristic though transient enhancement effect. This "stimulated acoustic emission" (SAE) works particularly well with the air-filled microbubbles, as used by Hauff and colleagues. It has proved a powerful method of studying passively targeted agents (4) but has not previously been used to image active targeting.
The authors come from a laboratory with more than 2 decades of experience in microbubble development. They used a cyanoacrylate-based agent, known from animal and human studies to passively target the spleen and liver but not the lymph nodes (5). As controls, they used both microbubbles with a control antibody and naked microbubbles without any antibody. They gave the agents intravenously to mice and dogs and studied SAE in tissues 30 minutes after injection, at which time the microbubbles had cleared from the blood pool. All microbubbles showed splenic uptake, but only those with L-selectin ligand antibodies were seen in lymph nodes. In addition, the location of the SAE in the lymph nodes corresponded to areas associated with high L-selectin ligand expression.
The Practice
Clinical use.—Although a relatively small preclinical study, this is an exciting indicator of future developments. A reliable lymph node–specific agent for use with US could help in the primary assessment of nodes in which malignancy is suspected. It could help to guide tissue sampling of nodes, which is commonly performed with US, by showing tumor foci as areas of intranodal defects. Surgical applications could include guiding of lymph node sampling. Such agents could be developed to help US-based sentinel node imaging strategies.
The authors have used an agent with a distinctive and strong acoustic signature, which may be a useful strategy for the imaging of targeted microbubbles because of its high sensitivity. In principle, it may be possible to detect a single microbubble by using the methods they describe.
However, considerable development work would be needed. Only part of the lymph node was enhanced, and it may be that another molecular target would work better. There are potential safety concerns in using deliberately high-power US to fragment microbubbles, as this can increase the chance of acoustic cavitation (6). The method they used to attach the antibody involves the use of streptavidin, which is antigenic, so another method of coupling the antibody and microbubble would be needed for human use.
Future opportunities and challenges.—Actively targeting microbubbles could be useful in many organs and tissues. In addition to the extensive scope for molecular imaging, it would help in the therapeutic uses of microbubbles. Antibody targeting could help in the site-specific delivery of genes and oligonucleotides, an emerging application for microbubble US (1,7).
Summary
The authors have described a lymph node–specific microbubble, the location of which can be distinctively mapped by using US, and they have demonstrated targeting to lymph nodes in vivo.
FOOTNOTES
See also the article by Hauff et al in this issue.
REFERENCES
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