Imaging Angiogenesis: Applications and Potential for Drug Development

Abstract

Recognition of the importance of angiogenesis to tumor growth and metastasis has led to efforts to develop new drugs that are targeted to angiogenic vasculature. Clinical trials of these agents are challenging, both because there is no agreed upon method of establishing the correct dosage for drugs whose mechanism of action is not primarily cytotoxic and because of the long time it takes to determine whether such drugs have a clinical effect. Therefore, there is a need for rapid and effective biomarkers to establish drug dosage and monitor clinical response. This review addresses the potential of imaging as a way to accurately and reliably assess changes in angiogenic vasculature in response to therapy. We describe the advantages and disadvantages of several imaging modalities, including positron emission tomography, x-ray computed tomography, magnetic resonance imaging, ultrasound, and optical imaging, for imaging angiogenic vasculature. We also discuss the analytic methods used to derive blood flow, blood volume, empirical semiquantitative hemodynamic parameters, and quantitative hemodynamic parameters from pharmacokinetic modeling. We examine the validity of these methods, citing studies that test correlations between data derived from imaging and data derived from other established methods, their reproducibility, and correlations between imaging-derived hemodynamic parameters and other pathologic indicators, such as microvessel density, pathology score, and disease outcome. Finally, we discuss which imaging methods are most likely to have the sensitivity and reliability required for monitoring responses to cancer therapy and describe ways in which imaging has been used in clinical trials to date.

Molecular profiling of angiogenesis with targeted ultrasound imaging: early assessment of antiangiogenic therapy effects

“…4,5,7,26). Molecular imaging may even be capable to indicate early therapy response of tumors (e.g., down-regulation of growth factor receptors) occurring before the change of tumor volume.…”

Ultrasound assessment of angiogenesis in a matrigel model in rats

“…In addition, MVD measurement is an invasive technique and representative tumor sampling is difficult due to tumor heterogeneity. Therefore, there is an acute need for developing imaging techniques that can quantitatively estimate angiogenesis in whole tumors, and in using these techniques to direct cancer therapy (McDonald and Choyke 2003;Miller et al 2005).…”

In vivo delivery of fluoresceinated dextrans to the murine growth plate: Imaging of three vascular routes by multiphoton microscopy

“…We propose that this differential behavior reflects potentially different physiological roles of the three vascular access routes during endochondral ossification. Understanding physiological differences among the three routes of vascular access to the growth plate has implications for understanding rate variables regulated through paracrine and systemic pathways during postnatal long bone growth, as well as for developing strategies for effective drug delivery to the growth plate (Miller et al, 2005).…”