Abstract

The objective of this study was to determine the utility of ^99mTc-3P-Arg-Gly-Asp (RGD₂) single photon emission computed tomography (SPECT)/computed tomography (CT) for noninvasive monitoring of integrin α_vβ₃-expression response to antiangiogenic treatment with linifanib. Linifanib or vehicle therapy was carried out in female athymic nu/nu mice bearing U87MG glioma (high α_vβ₃ expression) or PC-3 prostate (low α_vβ₃ expression) tumors at 12.5 mg/kg twice daily. The average tumor volume was 180 ± 90 mm³ the day prior to baseline SPECT/CT. Longitudinal ^99mTc-3P-RGD₂ SPECT/CT imaging was performed at baseline (–1 day) and days 1, 4, 11, and 18. Tumors were harvested at all imaging time points for histopathological analysis with H&E and immunohistochemistry. A significant difference in tumor volumes between vehicle- and linifanib-treated groups was observed after 4 days of linifanib therapy in the U87MG model. The percent injected dose (%ID) tumor uptake of ^99mTc-3P-RGD₂ peaked in the vehicle-treated group at day 11, while the %ID/cm³ tumor uptake decreased slowly over the whole study period. During the first 2 days of linifanib treatment, a rapid decrease in both %ID/cm³ tumor uptake and tumor/muscle ratios of ^99mTc-3P-RGD₂ was observed, followed by a slow decrease until day 18. No decrease in tumor uptake of ^99mTc-3P-RGD₂ or tumor volume was observed for either treatment group in the PC-3 model. Changes in tumor vasculature were confirmed by histopathological H&E analysis and immunohistochemistry. Longitudinal imaging using ^99mTc-3P-RGD₂ SPECT/CT may be a useful tool for monitoring the downstream biologic effects of linifanib therapy.