| Cancer is one of the leading causes of deaths in the U.S. and worldwide. One of the main obstacles for early detection and treatment of cancer is the lack of sensitive and tumor-specific probes. Currently, 18F-Fluorodeoxyglucose (18FDG) positron emission tomography (PET) imaging is one of the most common and powerful techniques in clinical use to detect and stage cancer. However, the result is only satisfactory on limited tumor types and can be associated with confusing false-positive findings. Angiogenesis, the formation of new blood vessels, is a common prerequisite for the development of a broad range of tumors and cancer metastases. Vascular endothelial growth factor (VEGF) is the most dominant pro-angiogenic factor and it's the only growth factor that has been found to be expressed throughout the whole tumor life cycle for a wide range of cancer types including metastasis. The goal of this project was to develop and validate a new generation of PET imaging biomarker (64Cu-bevacizumab) by targeting the VEGF released from cancer related tissue in order to not only accurately detect tumor in an earlier stage compared with 18FDG but also effectively decrease the false positive findings shown in 18FDG imaging.;The hypothesis of this project was that radiolabeled anti-VEGF antibody (64Cu-bevacizumab) could be used as a PET marker to detect a wide range of tumor types and metastasis at an earlier stage than 18FDG. And because of the difference in the physiological uptake mechanism with 18FDG, we also hypothesized that 64Cu-bevacizumab imaging will have fewer false-positive findings than 18FDG imaging and could effectively detect a broad range of tumors and metastasis in nude mice models.;The specific aims of this project were to (1) develop a chemical method to radiolabel anti-VEGF antibody, Bevacizumab, and the control antibody with 64Cu, achieving predefined radiochemical properties, good immunoreactivity, and in vitro stability; (2) to understand the pharmacokinetics, biodistribution and imaging properties of 64Cu-bevacizumab by performing studies in established pancreatic cancer xenograft and orthotopic mouse models (Mia Paca-2) and compare the result with standard 18FDG imaging; (3) to verify the generalizability of 64Cu-bevacizumab on tumor detection by performing microPET/CT imaging studies and evaluating the biodistribution and imaging properties in different cancer xenograft and orthotopic mouse models and compare the result with standard 18FDG imaging (BxPC3, H460, CACO-2, MDA-MB-231, LNCaP, and SKOV3); (4) to evaluate the ability and sensitivity of 64Cu-bevacizumab to detect metastatic tumor by performing microPET/CT imaging studies and evaluating the biodistribution and imaging properties in a breast cancer bone metastasis mouse model (MDA-MB-231) and compare the result with standard 18FDG imaging.;The conclusions of this study are 64 Cu-bevacizumab showed its superiority in tumor detection in 7 different human cancer mouse xenograft, orthotopic, and metastatic models over 18FDG. Experiment results demonstrated that 64Cu-bevacizumab can detect tumor earlier than 18FDG and showed fewer false positive findings in a series of pre-clinical studies. Since bevacizumab is a FDA approved drug, the results suggest that to apply this probe to human use for this purpose is highly possible. If so, this would result in early treatment and may possibly increase survival rate to various cancers. |
