Cyclooxygenase-2 targeted in vivo imaging of cancer

A59

Cyclooxygenase-2 (COX-2) enzyme is expressed in many malignant tumor types, even in very early stage pre-adenomas. Diagnostic imaging of cancer is still limited by the non-selective accumulation of imaging agents in normal tissues. In this regard, we have developed a novel COX-2-based imaging agent that is used as a tool for COX-2-targeted in vivo imaging of tumors with a >50:1 accumulation in the tumor over normal tissue. The fluorescent compound has adequate physicochemical properties to penetrate freely into living cells and allow direct imaging of COX-2 in four different mouse models: (a) liver metastasis model, (b) xenograft model, (c) C57BL/6 lung tumor model, and (d) min mouse intestinal polyp model. This imaging agent maintains adequate plasma concentration over a period of time sufficient for uptake into the target site for in vivo fluorescence imaging. Targeted COX-2 imaging and compound pharmacokinetics were assigned using bio-analytical methods that provided quantitative measurement of intact parent compound in the regions of interest. COX-2-targeted delivery was unambiguously confirmed by blocking the COX-2 active site with high affinity inhibitors in both in vitro and in vivo mouse models. It is noteworthy that in an in vivo mouse xenograft model, indomethacin blocked 92.6% (ѱ1.5%) of the COX-2 expressing tumor uptake of the lead compound. This novel strategy might be useful to develop tools to detect COX-2-expressing early stage human cancers using in vivo imaging techniques.