Division of Functional Imaging

Hirofumi Fujii, Izumi O. Umeda, Masayuki Yamaguchi, Mitsuyoshi Yoshimoto

Introduction

The Division of Functional Imaging actively investigates new imaging technique to disclose the nature of malignant tumors and to develop epoch-making therapeutic strategies for intractable cancer.

Our team and what we do

Our major imaging modalities are radionuclide imaging, optical imaging, and magnetic resonance (MR) imaging. Some experimental studies were performed using these imaging tests to develop unique imaging strategies to overcome malignant tumors.

Research activities

In the field of nuclear medicine, we are developing two kinds of new hypoxia imaging probes because in vivo visualization of tumor hypoxia greatly contributes to the optimization of cancer therapy. One group contains 99mTc-labeled compounds with unique retention mechanism in hypoxic areas in tumors. We obtained a new probe with modified chemical structure and, consequently, its tumor accumulation and tumor-to-background ratio after intravenous injection were greatly improved. Another group consisted of probes to image hypoxia inducible factor-1 (HIF-1)-positive areas in the tumor. HIF-1 mimic proteins that could be broken down in normoxic areas were labeled with radionuclides and they were administered to tumor-bearing mice intravenously. They accumulated in the tumor sufficiently, and their activity in tumors was imaged by SPECT/CT tests.

Multimodality in vivo imaging using radionuclides and over-1,000 nm near-infrared (OTN-NIR) fluorescence was also developed. YPO4nanoparticles (NPs) are OTN-NIR materials and we modified its surface with polyethylene glycol and radioactive 111In. By using these hybrid NPs, we could acquire in vivo multi-modality images of OTN-NIR and SPECT/CT in mice.

Boron neutron capture therapy (BNCT) is a kind of radiotherapy based on nuclear capture and fission reactions by 10B and low energy thermal neutrons. In BNCT, 10B-4-borono-L-phenylalanine (BPA) is commonly used as a 10B carrier. To estimate boron concentration and tumor to normal tissue ratios, 4-borono-2-18F-fluoro-phenylalanine (18F-FBPA) PET has been performed. However, there are several differences between PET using 18F-FBPA and BNCT using BPA. The first is administration dose. Compared to tracer dose of 18F-FBPA in PET, 250 - 500 mg/kg of BPA is administrated in BNCT. The second is the administration method. While BPA is administrated via continuous intravenous infusion (CIV), 18F-FBPA is administrated via bolus injection. We investigated usefulness of 18F-FBPA PET for predicting boron concentration in human tumor xenograft models. PET studies revealed that there was no difference of tumor uptake of 18F-FBPA between the bolus injection and that by the CIV. PET study also indicated that the tumor uptake of 18F-FBPA by the bolus injection well correlated with that of BPA by the CIV. Therefore, we believe that 18F-FBPA PET could estimate the therapeutic effects based on the boron concentration in tumor and tumor to normal tissue ratios.

In the field of magnetic resonance (MR) imaging, some experimental and clinical studies were done using two kinds of scanners, a 9.4 T scanner dedicated to small animal imaging and a 3.0 T whole-body scanner.

We are focusing on the following two topics: (1) a novel application of superparamagnetic iron oxide (SPIO)-enhanced MR imaging of the liver cancer, and (2) MR spectroscopy (MRS) for in vivo monitoring of oncometabolite levels in malignant tumors. In SPIO-enhanced MR imaging research, we developed a novel technique that can precisely visualize the treatment margins of hepatic tumors after radiofrequency ablation (RFA) as well as radiation therapies. Since our SPIO-enhanced MR imaging technique can sensitively detect treatment-related signal changes in the liver parenchyma surrounding hepatic tumors, the treatment margins are instantly recognizable more earlier than currently-available techniques; therefore, we contend that this technique indeed assists clinicians in predicting the responses of liver cancer lesions to these therapies. In MRS research, we tested an ultra-short echo-time MRS technique to sensitively detect the signals of 2-hydroxyglutarate (2HG) in glioma and chondrosarcoma animal models in collaboration with Dr. Kitabayashi at the NCC Research Institute. Our data demonstrated that this MRS technique can detect 2HG signals only in tumors with isocitrate dehydrogenase-1 (IDH-1) mutation, but not in those with wild type IDH-1. Currently, we intend to improve the sensitivity of this MRS technique to monitor the reduction of 2HG levels during the treatment period with IDH-1 mutant inhibitors.

Education

Some graduate school students took part in our studies and received doctor or master degrees in the field of medicine and related sciences.

Future prospects

We will develop our research projects to translate our research products into clinical practice.