ABSTRACT
We describe a new generation of tracers for molecular imaging of the cell surface receptors for epidermal growth factor (EGF). These receptors play a key role in the progression of many tumors and are major drug development targets. Our tracers are based on a recombinant human EGF expressed with a cysteine-containing tag that enables facile site-specific radiolabeling with (99m)Tc for single photon emission computed tomography or site-specific conjugation of (64)Cu PEGylated chelators for positron emission tomography. These tracers retain EGF activities in vitro and display selective and highly specific focal uptake in tumors in vivo. We expect that nuclear imaging of EGF receptors with these tracers will be useful for clinical diagnosis, therapeutic monitoring, and development of new drugs and treatment regimens.
Subject(s)
Epidermal Growth Factor/metabolism , ErbB Receptors/analysis , Protein Multimerization , Protein Structure, Quaternary , Animals , Autoradiography , Binding Sites , Cell Line, Tumor , Chelating Agents/chemistry , Cystine/chemistry , Epidermal Growth Factor/chemistry , Epidermal Growth Factor/pharmacokinetics , ErbB Receptors/metabolism , Heterocyclic Compounds, 1-Ring/chemistry , Humans , Male , Mice , Organotechnetium Compounds/chemistry , Polyethylene Glycols/chemistry , Positron-Emission Tomography , Rats , Staining and Labeling , Substrate Specificity , Tissue Distribution , Tomography, Emission-Computed, Single-PhotonABSTRACT
We describe a new generation of protein-targeted contrast agents for multimodal imaging of the cell-surface receptors for vascular endothelial growth factor (VEGF). These receptors have a key role in angiogenesis and are important targets for drug development. Our probes are based on a single-chain recombinant VEGF expressed with a cysteine-containing tag that allows site-specific labeling with contrast agents for near-infrared fluorescence imaging, single-photon emission computed tomography or positron emission tomography. These probes retain VEGF activities in vitro and undergo selective and highly specific focal uptake into the vasculature of tumors and surrounding host tissue in vivo. The fluorescence contrast agent shows long-term persistence and co-localizes with endothelial cell markers, indicating that internalization is mediated by the receptors. We expect that multimodal imaging of VEGF receptors with these probes will be useful for clinical diagnosis and therapeutic monitoring, and will help to accelerate the development of new angiogenesis-directed drugs and treatments.
