Rapid detection of hypoxia-inducible factor-1-active tumours: pretargeted imaging with a protein degrading in a mechanism similar to hypoxia-inducible factor-1[alpha]

Hypoxia-inducible factor-1 (HIF-1) plays an important role in malignant tumour progression. For the imaging of HIF-1-active tumours, we previously developed a protein, POS, which is effectively delivered to and selectively stabilized in HIF-1-active cells, and a radioiodinated biotin derivative, (3-^sup 123^I-iodobenzoyl)norbiotinamide (^sup 123^I-IBB), which can bind to the streptavidin moiety of POS. In this study, we aimed to investigate the feasibility of the pretargeting method using POS and ^sup 123^I-IBB for rapid imaging of HIF-1-active tumours. Tumour-implanted mice were pretargeted with POS. After 24 h, ^sup 125^I-IBB was administered and subsequently, the biodistribution of radioactivity was investigated at several time points. In vivo planar imaging, comparison between ^sup 125^I-IBB accumulation and HIF-1 transcriptional activity, and autoradiography were performed at 6 h after the administration of ^sup 125^I-IBB. The same sections that were used in autoradiographic analysis were subjected to HIF-1[alpha] immunohistochemistry. ^sup 125^I-IBB accumulation was observed in tumours of mice pretargeted with POS (1.6%ID/g at 6 h). This result is comparable to the data derived from ^sup 125^I-IBB-conjugated POS-treated mice (1.4%ID/g at 24 h). In vivo planar imaging provided clear tumour images. The tumoral accumulation of ^sup 125^I-IBB significantly correlated with HIF-1-dependent luciferase bioluminescence (R = 0.84, p < 0.01). The intratumoral distribution of ^sup 125^I-IBB was heterogeneous and was significantly correlated with HIF-1[alpha]-positive regions (R = 0.58, p < 0.0001). POS pretargeting with ^sup 123^I-IBB is a useful technique in the rapid imaging and detection of HIF-1-active regions in tumours. [PUBLICATION ABSTRACT]