This study evaluated the detection of
tumors using in vivo imaging with a commercially available and systemically administered
protease-activatable
fluorescent probe, ProSense. To this end, we analyzed the delivery and uptake of ProSense as well as the target
protease and its cellular source in a mouse xenograft
tumor model. In vivo and ex vivo multi wavelength imaging revealed that ProSense signals accumulated within
tumors, with preferential distribution in the vascular leakage area that correlates with vasculature development at the
tumor periphery. Immunohistochemically,
cathepsin B, which is targeted by ProSense, was specifically localized in macrophages. The codistribution of
tenascin C immunoreactivity and
gelatinase activity provided evidence of tissue-remodeling at the
tumor periphery. Furthermore, in situ zymography revealed extracellular ProSense cleavage in such areas. Colocalization of
cathepsin B expression and ProSense signals showing reduction by addition of
cathepsin B inhibitor was confirmed in cultured macrophage-derived RAW264.7 cells. These results suggest that increased tissue-remodeling activity involving infiltration of macrophages is a mechanism that may be responsible for the
tumor accumulation of ProSense signals in our xenograft model. We further confirmed ProSense signals at the
tumor margin showing
cathepsin B(+) macrophage infiltration in a rat colon
carcinogenesis model. Together, these data demonstrate that systemically administered
protease-activatable probes can effectively detect
cancer invasive fronts, where tissue-remodeling activity is high to facilitate neoplastic cell invasion.