Contrast ultrasound could play 2 roles in angiogenesis – targeted microbubbles could be used to monitor the presence and development of new blood vessels, and microbubbles could also be used to deliver drugs or genes to promote and maintain an angiogenic response. This latter role will be discussed further below. Imaging angiogenesis has utilized agents that have been targeted against integrins (such as Inhibitors,research,lifescience,medical αv -integrins like αvβ3 or αvβ5), against growth factors or their receptors (e.g. vascular endothelial growth factor or VEGF2 receptors), and against endothelial cell markers (such as VCAM-1). The angiogenic models that have been used for imaging

include tumor neovessels, Small molecule library matrigel plugs impregnated with fibroblast growth factor-2 (FGF-2) to stimulate angiogenesis development from surrounding vessels, and ischemia models. For example,

microbubbles bearing antibodies to VEGF2 receptor have been shown to enhance murine breast Inhibitors,research,lifescience,medical cancer models,33) contrast agents conjugated to small peptides which have strong affinity integrins like the arginine-glycine-aspartate (RGD) containing disintegrin echistatin have been used to enhance human squamous cell carcinoma implanted in nude mice,34) or arginine-arginine-leucine peptide Inhibitors,research,lifescience,medical has been used to detect Clone C and PC3 tumors in mice.35) The microbubbles selectively adhere to tumor-derived rather normal endothelium, which suggests that targeted contrast ultrasound has the potential to be used to characterize tumor angiogenesis, and subsequently to monitor antitumor or antiangiogenic therapies. Inhibitors,research,lifescience,medical Fig. 5 shows the

ability of targeted agents to detect neovessels in a murine model using a Matrigel plug impregnated with FGF-2 which stimulates angiogenesis from surrounding vessels. The microbubbles were conjugated with a monoclonal antibody against αv – integrins and produced Inhibitors,research,lifescience,medical significant enhancement of angiogenesis that had developed around the periphery of the plug (Fig. 5B).36) Similar success was shown using microbubbles conjugated to RGD peptide containing disintegrin echistatin (Fig. Ergoloid 5C).36),37) Conversely, no signal enhancement was noted when imaging was performed using a non-specific isotype antibody (Fig. 5A).36) Fig. 5 Imaging of neovessels in a matrigel plug using microbubbles conjugated to isotype antibodies (control, A), to monoclonal antibodies directed against αv (B), and echistatin (C). See text for details. Redrawn from Leong-Poi et al.36) Targeted microbubbles and ischemia models have been used to evaluate the role of angiogenesis in improving perfusion to ischemic tissue, and have also been used to assess the role of growth factors on enhancing angiogenesis.