Targeting Aminophospholipids Exposed on Tumor Endothelium for Tumor Imaging

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Targeting Aminophospholipids Exposed on Tumor Endothelium for Tumor Imaging

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Title: Targeting Aminophospholipids Exposed on Tumor Endothelium for Tumor Imaging
Author: Stafford, Jason Hugh
Abstract: Advances in noninvasive imaging of human cancer are crucial to improving diagnosis and therapeutic planning. My project was aimed at developing novel imaging agents that target the aminophospholipidsphosphatidylserine (PS) and phosphatidylethanolamine (PE). PS and PE arenormally intracellular, but become exposed on the surface of tumor endothelial cells (EC). Anti-tumor therapies promote exposure of PS and PE on tumor EC and the tumor cells as well. Therefore, I tested the hypothesis that 1N11, a PS-binding antibody, and duramycin, a PE-binding peptide, could function as tumor imaging agents. I labeled the F(ab’)2 fragment of 1N11 with the near-infrared fluophore 800CW for optical imaging and the positron emitting isotope iodine-124 (124I) for PET imaging. 800CW-1N11 F(ab’)2 clearly imaged subcutaneous and orthotopic U87 gliomas growing in mice with optimal tumor contrast obtained at 24 h post-injection (p.i.). Uptake of 800CW-1N11 F(ab’)2 was approximately 2-fold higher in irradiated U87 tumors. 124I-1N11 F(ab’)2 clearly imaged subcutaneous and orthotopic PC3 prostate carcinomas growing in mice with optimal tumor contrast obtained at 48 hr p.i. Importantly, 800CW- and 124I-1N11 F(ab’)2 exhibited low uptake in non-target organs (i.e. liver and kidneys). Unlike PS, PE had not been established as a specific marker of tumor vasculature in the literature. To demonstrate PE was such a marker, I biotinylated duramycin, characterized its binding properties, and used it to determine the distribution of PE on EC in vitro and in vivo. Exposure of cultured EC to hypoxia, acidity, reactive oxygen species, or irradiation resulted in the formation of membrane blebs that were intensely PE-positive. When biotinylated duramycin was intravenously injected into tumor-bearing mice it preferentially localized to the luminal surface of the vascular endothelium in multiple tumor models. PE-positive vessels were observed in and around hypoxic regions of the tumor. With the exception of intertubular vessels of the kidney, normal vessels remained unstained. I also conjugated duramycin to 800CW and used it for optical imaging of RM-9 and TRAMP prostate carcinomas. These results demonstrate that both 1N11 and duramycin can be used to image a variety of tumors and warrant further study as imaging agents. [Keywords" cancer, imaging, phospholipids, antibodies, peptides, optical, PET, phosphatidylserine, phosphatidylethanolamine, vasculature]
URI: http://hdl.handle.net/2152.5/1038
Date: 2012-07-20

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