To demonstrate the utility of our method for

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To demonstrate the utility of our method for clinically relevant PET imaging we performed longitudinal studies using a radiola#beled 18F-PMT10 (26). Mice were implanted subcutaneously with LS174T xenografts, and once tumors had grown to approxi#mately 1 cm in diameter, these mice were injected with 30 g of �� TCO-antibody against A33 (also labeled with VT680 fluoro#phore). After allowing 24 h for accumulation and clearance of the TCO-modified antibody, 18F-PMT10 was injected (30 g; �� 150 Ci). Cycloaddition of 4 mCi of TCO-18F to 60 g of dextran �� �� proceeded cleanly, leading to an 89.2% decay corrected radioche#mical yield of 18F-PMT10. This construct was used for all PET/ Computed Tomography (CT) and subsequent autoradiography experiments. PET/CT scans were initiated 3 h after injection of 18F-PMT10. The images revealed significant renal clearance of PMT10 as well as widespread tissue distribution. Fig. 4A shows one representative axial slice from the PET/CT reconstruction. Compared to control mice which were administered antibodies lacking TCO, there was significant accumulation of signal in the vascularized region of the tumor mediated by the in vivo TCO/Tz reaction. To investigate further, mice were euthanized 3 h after injection, the tumors were excised, and 1 mm slices were imaged to determine the extent of cycloaddition. Near infrared fluorescence was used to determine antibody/TCO localization and autoradiography was used to reveal the 18F-PMT10. Fig. 4B shows two representative tumor slices. The localization patterns of the chemical probes were distinct and often showed greatest activity in the periphery of the tumor, likely reflecting the necrotic nature of the tumor core. Comparison of the pattern to the lo#calization of the fluorescent antibody demonstrated good coloca#lization, indicating that the Tz probe was primarily localized to the site of TCO binding. Tumors from mice which were adminis#tered the control antibody lacking reactive TCO showed much lower uptake of Tz and a lack of correlation to antibody/TCO fluorescence signal. We also tested for biomarker specificity with mice simulta#neously implanted with LS174T tumors and A431 tumors which lack expression of the A33 glycoprotein epitope (27). Mice were administered anti-A33 TCO antibody and 18F-PMT10 as pre#viously described and imaged using PET/CT. Fig. 4C shows one representative coronal slice from the PET/CT reconstruction. LS174T tumors can be clearly visualized whereas the control A431 tumor shows much lower Tz uptake. Autoradiography of excised tumor slices further demonstrate the greater uptake of Tz in biomarker positive LS174T tumors vs. the control A431 tumors (Fig. 4D).
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  • Summer '14
  • Cavusgil

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