Here we used rational and combinatorial methods to engineer peptide and protein ligands that target integrin and vascular endothelial growth factor receptors with high (pM-nM) binding affinity. These receptors are important clinical targets as they are overexpressed in solid tumors or the tumor vasculature and mediate angiogenesis and metastasis. We have conjugated these receptor-targeting ligands to near-infrared fluorescence (NIRF) imaging probes and radiolabels for positron emission tomography (PET) and used them to image tumors in human tumor mouse xenograft models. We showed that tumor uptake of these imaging probes is highly dependent on their receptor binding affinity, and unlike other integrin targeting agents these probes exhibit low non-specific liver uptake. Next, we prepared peptide conjugates that contain dual-labels for multimodal imaging and used them to simultaneously image tumors by NIRF and PET imaging; such probes would be useful in the clinic for image-guided surgery. In addition, we have conjugated these receptor-targeting ligands to gas-filled echogenic microspheres (microbubbles) and showed that they could be used for ultrasound imaging in a murine model of tumor angiogenesis.

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