Showing papers by "Shinae Kizaka-Kondoh published in 2011"

PET imaging of hypoxia-inducible factor-1-active tumor cells with pretargeted oxygen-dependent degradable streptavidin and a novel 18F-labeled biotin derivative.

Abstract: We aimed to evaluate the feasibility of using streptavidin–biotin-based pretargeting for positron emission tomography (PET) imaging of hypoxia-inducible factor (HIF)-1-active tumors. We used POS, a genetically engineered form of streptavidin that selectively stabilizes in HIF-1-active cells, and (4-18F-fluorobenzoyl)norbiotinamide (18F-FBB), a radiolabeled biotin derivative, for performing a biodistribution study and for PET imaging. The tumoral 18F-FBB accumulation was compared to the HIF-1-dependent luciferase bioluminescence and HIF-1α immunohistochemical signal. 18F-FBB accumulation was observed in POS-pretargeted tumors in mice (2.85 ± 0.55% injected dose per gram at 3 h), and clear PET images were obtained at the same time point. The tumoral 18F-FBB accumulation positively correlated with luciferase bioluminescence (R = 0.72, P < 0.05), and most of the area showing 18F-FBB accumulation corresponded to HIF-1α-positive areas. Pretargeting with POS and 18F-FBB is an effective approach for PET imaging of HIF-1-active areas in tumors.

Evaluation of [125I]IPOS as a molecular imaging probe for hypoxia-inducible factor-1-active regions in a tumor: Comparison among single-photon emission computed tomography/X-ray computed tomography imaging, autoradiography, and immunohistochemistry

Abstract: To image hypoxia-inducible factor-1 (HIF-1)-active tumors, we previously developed a chimeric protein probe ([(123/125) I]IPOS) that is degraded in the same manner as HIF-1α under normoxic conditions. In the present study, we aim to show that the accumulation of radioiodinated POS reflects the expression of HIF-1. In vivo single-photon emission computed tomography (SPECT)/X-ray CT (CT) imaging, autoradiography, and double-fluorescent immunostaining for HIF-1α and pimonidazole (PIMO) were carried out 24 h after the injection of [(125) I]IPOS. Tumor metabolite analysis was also carried out. A tumor was clearly visualized by multi-pinhole, high-resolution SPECT/CT imaging with [(125) I]IPOS. The obtained images were in accordance with the corresponding autoradiograms and with the results of ex vivo biodistribution. A metabolite analysis revealed that 77% of the radioactivity was eluted in the macromolecular fraction, suggesting that the radioactivity mainly existed as [(125) I]IPOS in the tumors. Immunohistochemistry revealed that the HIF-1α-positive areas and PIMO-positive areas were not always identical, only some of the regions were positive for both markers. The areas showing [(125) I]IPOS accumulation were positively and significantly correlated with the HIF-1α-positive areas (R = 0.75, P < 0.0001). The correlation coefficient between [(125) I]IPOS-accumulated areas and HIF-1α-positive areas was significantly greater than that between the [(125) I]IPOS-accumulated areas and the PIMO-positive areas (P < 0.01). These findings indicate that [(125) I]IPOS accumulation reflects HIF-1 expression. Thus, [(123/125) I]IPOS can serve as a useful probe for the molecular imaging of HIF-1-active tumors.

Detection of the Onset of Ischemia and Carcinogenesis by Hypoxia-Inducible Transcription Factor-Based In Vivo Bioluminescence Imaging

Abstract: An animal model for the early detection of common fatal diseases such as ischemic diseases and cancer is desirable for the development of new drugs and treatment strategies. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that regulates oxygen homeostasis and plays key roles in a number of diseases, including cancer. Here, we established transgenic (Tg) mice that carry HRE/ODD-luciferase (HOL) gene, which generates bioluminescence in an HIF-1-dependent manner and was successfully used in this study to monitor HIF-1 activity in ischemic tissues. To monitor carcinogenesis in vivo, we mated HOL mice with rasH2 Tg mice, which are highly sensitive to carcinogens and are used for short-term carcinogenicity assessments. After rasH2-HOL Tg mice were treated with N-methyl-N-nitrosourea, bioluminescence was detected noninvasively as early as 9 weeks in tissues that contained papillomas and malignant lesions. These results suggest that the Tg mouse lines we established hold significant potential for monitoring the early onset of both ischemia and carcinogenesis and that these lines will be useful for screening chemicals for carcinogenic potential.