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Science to Practice |
1 Molecular Imaging Program, National Cancer Institute, Bldg 10, Rm B3B69, Bethesda, MD 20892-1002 pchoyke@nih.gov
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Angiogenesis is critical to the growth of cancer, and as a consequence, it has become a target for new drugs aimed at inhibiting the development of neovasculature. Accordingly, there is increasing interest in the imaging of angiogenesis as a means of monitoring the effects of these inhibitors (1). Dynamic contrast agent–enhanced magnetic resonance (MR) imaging with low-molecular-weight gadolinium chelates has been shown to enable radiologists to predict outcomes of angiogenic inhibition early after it has begun (2). Most dynamic contrast-enhanced MR imaging techniques use a pharmacokinetic model with two or more compartments; in theory, this model can be used to calculate values for vessel permeability and fractional blood volume. In fact, these parameters represent a complex mixture of flow and permeability (3). Contrast agents with a high molecular weight are better for deconvolution of vessel permeability and vascular volume. It is unclear, however, what diameter contrast agent gives the most reliable results. Moreover, many macromolecular contrast agents exhibit a range of molecular diameters due to protein binding and clumping. In this issue of Radiology, de Lussanet et al (4) demonstrate that gadolinium-labeled dendrimers, which vary only in molecular weight but are otherwise chemically identical, reveal the effects of molecular size on the measurement of tumor angiogenesis.
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The authors synthesized four different gadolinium-labeled dendrimer contrast agents of varying molecular weight (0.7, 3, 12, and 51 kDa) and injected them in mice with implanted colon cancers. Each set of dendrimers was homogeneous in size and varied in diameter from less than 1 nm to between 5 and 6 nm. The measured permeability and vascular volume decreased with increasing molecular size. Interestingly, the decrease in vascular volume was not linearly related to molecular weight but demonstrated an abrupt decrease between 3 and 12 kDa, which suggests that in this range of molecular weights, blood volume can be differentiated with more accuracy. As with many in vivo studies, it is virtually impossible to independently validate these results with other methods. In vitro biomarkers of angiogenesis, which provide indirect validation, were not obtained in this study. Additionally, molecular weight should not be equated with molecular diameter, since molecular folding can alter diameter. Thus, although the results obtained by de Lussanet et al (4) are not definitive, they are highly suggestive that permeability and blood volume can be distinguished with greater accuracy by using high-molecular-weight dendrimer contrast agents.
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Clinical use.—The major implication of this work is that nanoparticulate contrast agents synthesized to a precise size allow more accurate and independent monitoring of tumor vessel permeability and vascular volume. Some vascular-targeted therapies primarily affect vessels, while others preferentially target vessel permeability; nanoparticulate contrast agents may allow physicians to distinguish the effects of these targeted therapies. In the future, perhaps on the basis of the dendrimer chemistry presented in the report by de Lussanet et al (4), such agents may play a role in monitoring tumor angiogenesis during therapy.
Future opportunities and challenges.—Extensive safety testing and pharmacokinetics are required before Phase I trials are possible. Moreover, the pharmaceutical company business model for developing new contrast agents requires that there be a sufficient number of potential clinical uses to justify the costs of drug development and testing. Fortunately, there is a growing list of potential indications for macromolecular contrast agents, including imaging of tumors, liver, vessel wall, sentinel nodes, and organ perfusion, that could make the development of such contrast agents more appealing to pharmaceutical companies. Radiologists should be aware of the importance of developing new contrast agents to improve the specificity of imaging.
Summary
MR contrast agents with high molecular weights are more reliable in the differentiation of vascular permeability and blood volume within tumors than the low-molecular-weight contrast agents currently in use. Meanwhile, experimental contrast agents that are targeted to specific endothelial cell surface markers on the surface of angiogenic vessels are under development and may ultimately provide a more accurate reflection of vascular response to therapy.
FOOTNOTES
See also the article by de Lussanet et al in this issue.
REFERENCES
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