| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Science to Practice |
Department of Radiology Beth Israel Deaconess Medical CenterOne Deaconess Rd Boston, MA 02215 jkruskal{at}bidmc.harvard.edu
SUMMARY
By conjugating a monoclonal antibody specific for a surrogate marker of angiogenesis to a contrast-enhancing microbubble, US was used to indirectly image this receptor in two different tumor types growing in live mice.
THE SETTING
The widespread clinical introduction of antiangiogenic therapies continues to stimulate a search for surrogate imaging biomarkers for monitoring treatment response. One promising approach takes advantage of the ability of ultrasonographic (US) contrast material–enhancing microbubbles to be targeted to specific endothelial cell surface receptors in vivo. Specific endothelial cell ligands (such as monoclonal antibodies or engineered peptides) can be conjugated to the outer shell of contrast-enhancing microbubbles to selectively direct the bubbles to receptors residing in specific vascular beds, permitting in vivo imaging of angiogenesis at the cellular and molecular level. In this issue of Radiology, Willmann et al (1) have used US to detect contrast-enhancing microbubbles targeted to specific receptors on newly formed endothelial cells in tumors growing in live mice to indirectly image angiogenic activity.
|
Site-directed targeting and retention of contrast-enhancing microbubbles were achieved by conjugating monoclonal antibodies to a bubble shell (1). The antibodies selected the target, vascular endothelial growth factor receptor 2 (VEGFR2), a high-affinity tyrosine kinase receptor and member of the VEGF family of proteins that are critical regulators of vasculogenesis, angiogenesis, and endothelial cell differentiation and proliferation (2). The ligand VEGF is a proangiogenic cytokine which is expressed in many tumor cells and activated macrophages. Through interaction with its receptors, VEGF acts selectively on vascular endothelial cells to support angiogenesis by increasing vessel permeability to circulating macromolecules and stimulating their replication (2).
The authors demonstrated binding to VEGF receptors on tumor cells in vitro, and to tumor-associated endothelium in vivo (1). It is possible that there may be many unimaged receptors on tumor cells in vivo. An interesting project would be to characterize the presence of these receptors on tumor and endothelial cells during the various phases of angiogenesis, since imaging of targeted microbubbles may underestimate the extent of receptor expression.
Other putative biomarkers of angiogenesis have been imaged in vivo. As an example, expression of the 
vβ3 integrin which is only expressed on newly formed endothelial cells (3) has been probed by using magnetic resonance (MR) imaging–visible liposomes, microbubbles, and even particles loaded with therapeutic agents (4).
Site-directed delivery relies on the presence of patent tumor microvessels, so this technique is likely to be limited to imaging dormant or avascular tumors, or micrometastases prior to their transformation to an angiogenic phenotype.
THE PRACTICE
Clinical use.—Since most currently available microbubbles share hemodynamic properties with erythrocytes, targeting is currently possible only to sites in the vascular compartment, such as areas of inflammation and reperfusion, sites of thrombus formation, and angiogenesis (5,6). By conjugating engineered peptides or monoclonal antibodies to the bubble shell, receptors expressed on newly formed blood vessels in tumors can be targeted, allowing the different stages of angiogenesis to be indirectly imaged and characterized. Such information can be used to identify and characterize the degree and extent of angiogenic behavior. An advantage of probing expression of the VEGF receptor is that drugs such as becacizumab (Avastin; Genentech, San Francisco, Calif) are being used clinically to inhibit this receptor. In theory, US imaging can be used to assess suitability for selecting a specific antiangiogenic drug, and for monitoring response to therapy. The method described by Willmann et al (1) provides a proof of principle that contrast-enhanced US imaging can be used to document the presence of VEGF receptors prior to anti-VEGF therapy being instituted.
Future opportunities and challenges.—The technology described by Willmann et al (1) offers additional opportunities for translation research. One such opportunity is to target sites with therapeutic microbubble-carrying payloads for local US-guided release and delivery into cells. Through unclear mechanisms, US exposure is known to enhance delivery and transfection of DNA into tumor cells. Other opportunities exist for enhancing the sensitivity of detecting specific cell surface receptors, possibly through development of signal enhancers, and for delivering larger quantities of desired therapeutic agents to these sites. This will likely require that ligands be engineered to maximize targeting and minimize nonspecific binding to other cells. Methods for enhancing intracellular uptake of cell surface–bound agents should also be explored. It is also important to examine changes in the acoustic properties of microbubbles when carrying drugs in their cores.
It is also important to compare this technology with promising alternate imaging modalities, such as CT perfusion (7) and MR imaging with arterial spin-labeling (8). Several challenges must first be overcome before such technology is introduced into routine clinical practice. The method for conjugating ligands to bubble shells must be optimized to minimize potential human toxicities. It is also important to compare the avidity of different ligands for specific receptors. For example, expression and release of VEGF and the density of VEGF2 receptors may vary between tumor types, between cells of the same tumor, and in response to treatment. It is also possible that panspecific ligands can be engineered to detect a panel of relevant receptors when selecting therapies. As this field expands, it is vital that the in vitro data be translated to in vivo models and that advantage is taken of the ability of US to image spatial heterogeneity in three dimensions.
FOOTNOTES
See also the article by Willmann et al in this issue.
References
Related Article
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| RADIOLOGY | RADIOGRAPHICS | RSNA JOURNALS ONLINE |
