Multimodality Imaging of Tumor Vasculature and Metabolism
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Cancer is the second leading cause of death in America. A number of abnormal features in tumor vasculature and metabolism have been identified as imaging biomarkers to detect tumor boundary, provide physiological information, predict treatment response and guide surgeries. In chapter 2, longitudinal MRI was applied to monitor the initiation and development of intracranial tumors and assess the changes in tumor vascular volume and permeability in a mouse model of breast cancer brain metastases. Using a 9.4T system, high resolution anatomic MRI and dynamic susceptibility contrast (DSC) perfusion MRI were acquired at different time points after an intracardiac injection of brain-tropic breast cancer MDA-MB231-BR-EGFP (231-BR) cells. DSC MRI revealed that relative cerebral blood volume (rCBV) of metastatic tumors was significantly lower than that of contralateral normal brain. Intriguingly, longitudinal measurements showed that rCBV of individual metastases at early stage was similar to, but became significantly lower than that of their healthy counterparts with tumor growth. The rCBV data were in agreement with histological analysis of microvascular density (MVD). In chapter 3, 20 nm super-paramagnetic iron oxide (SPIO) particles were conjugated with a novel monoclonal antibody PGN635 to image the exposed phosphatidylserine (PS) on the tumor vascular endothelial cells and evaluate the enhanced exposure of PS as a result of radiation therapy in mice subcutaneous tumors. Both in vitro and in vivo studies verified the binding of SPIO-PGN635 and showed elevated PS exposure upon irradiation. In the subcutaneous tumor models, the distribution of the contrast appeared to be inhomogeneous across the tumors. Sparse signal loss was observed on the T2 weighted images after the administration of SPIO-PGN635. The signal loss fraction indicated significantly more increase in the irradiated tumor compared to the non-irradiated side. Prussian blue staining confirmed the accumulation of SPIO-PGN635 in the tumors along the blood vessels. Control and blocking studies were conducted to validate antigen specificity. It is recognized that cancer cells exhibit highly elevated glucose metabolism compared to non-tumor cells. In chapter 4, I have applied in vivo optical imaging to study dynamic uptake of a near-infrared dye-labeled glucose analogue, 2-deoxyglucose (2-DG) by orthotopic glioma in a mouse model. Dynamic fluorescent imaging revealed significantly higher signal intensity in the tumor side of the brain than the contralateral normal brain 24 h after injection. Even stronger contrast was achieved by removing the scalp and skull of the mice. In contrast, a control dye, IRDye800CW carboxylate, showed little difference. Ex vivo fluorescence imaging performed on ultrathin cryosections of tumor bearing whole brain revealed distinct tumor margins. Microscopic imaging identified cytoplasmic locations of the 2-DG dye in tumor cells.
Magnetic Resonance Imaging