Annual Report 2019
Division of Functional Imaging
Hirofumi Fujii, Masayuki Yamaguchi, Mitsuyoshi Yoshimoto
Introduction
The Division of Functional Imaging actively investigates new imaging techniques to disclose the nature of malignant tumors and develop epoch-making therapeutic strategies for intractable cancers.
The Team and What We Do
Our major imaging modalities include radionuclide (RN) 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
As for nuclear medicine studies, we were mainly engaged in radionuclide therapy, especially targeted alpha therapy using alpha-emitters such as Ac-225 and At-211, which is attracting attention as a new promising cancer treatment strategy. We previously reported that SPECT imaging using In-111 labeled RGD peptide, which is an αvβ3 imaging agent, could successfully detect small tumors in a pancreatic carcinogenesis model, indicating that RGD-containing peptides would be possible candidates as a radionuclide carrier for pancreatic cancer. We have tried to synthesize Ac-225 labeled RGD peptide. We obtained the Ac-225 labeled RGD peptide with high specific activity by HPLC purification. Further modification of the labeling conditions allows us to obtain the Ac-225 labeled RGD peptide with high specific activity without HPLC purification. In a therapeutic experiment using BxPC-3 xenograft mice, the Ac-225 labeled RGD successfully suppressed the tumor growth. The 65 kBq of the Ac-225 labeled RGD significantly inhibited the tumor growth, while a decrease in body weight was observed from 40 days after the administration. In blood toxicity, the Ac-225 labeled RGD decreased in white blood cells and platelets. Liver toxicity dose-dependently appeared while kidney toxicity was not obvious. These results suggested that the Ac-225 labeled RGD has great potential to treat intractable pancreatic cancers. We will make further efforts to investigate administration protocols to reduce the radiotoxicity.
As for MRI studies, we have been developing a non-invasive MR imaging technique for evaluating the tumor microenvironment, such as blood perfusion, vascular permeability, and molecular diffusion in tumor lesions. This year, we have been intensively conducting animal experiments by using breast cancer mouse models to make sure that our imaging technique can detect the changes in the tumor microenvironment before and after administration of a novel chemotherapeutic agent, which has is capable of remodeling tumor micro-vasculatures in addition to its cytotoxic effect. We confirmed that our MRI technique can clearly visualize tumor areas where tumor perfusion, vascular permeability, and molecular diffusion are significantly changing during chemotherapy. Notably, the significant increase in tumor perfusion and vascular permeability are expanding from the peripheral part to the central part of the subcutaneously xenografted tumors, suggesting that the distribution of functional micro-vessels might have expanded to where tumor tissues were originally poorly perfused. Now we are trying to translate this discovery to the clinic by conducting a clinical trial in which patients will undergo serial MRI examinations during treatment with this chemotherapeutic agent.
In addition to these kinds of single modality studies, we are also investigating multi-modality imaging tests. We are now developing a new contrast agent that is available for both MR imaging and optical imaging to sensitively detect HER2-positive breast cancer cells in vivo. This project is now in the very early stage; however, our initially obtained results are very promising.
Education
Some graduate school students took part in our studies and received doctoral or master degrees in fields of medicine and related sciences. We also gave some lectures and seminars and provided educational support to medical doctors and students.
Future prospects
We will develop our research projects to translate our research products into clinical practice.
List of papers published in 2019
Journal
1. Furuta T, Yamaguchi M, Minami M, Abe O, Fujii H. Treatment margins in radiotherapy for liver tumors visualized as T2*-hypointense areas on SPIO-enhanced MRI at 9.4 T. MAGMA, 2020
2. Machida Y, Nakagawa M, Matsunaga H, Yamaguchi M, Ogawara Y, Shima Y, Yamagata K, Katsumoto T, Hattori A, Itoh M, Seki T, Nishiya Y, Nakamura K, Suzuki K, Imaoka T, Baba D, Suzuki M, Sampetrean O, Saya H, Ichimura K, Kitabayashi I. A Potent Blood-Brain Barrier-Permeable Mutant IDH1 Inhibitor Suppresses the Growth of Glioblastoma with IDH1 Mutation in a Patient-Derived Orthotopic Xenograft Model. Mol Cancer Ther, 19:375-383, 2020
3. Yamaguchi M, Ohnuki K, Hotta K, Fujii H. MR signal changes in superparamagnetic iron oxide nanoparticle-labeled macrophages in response to X irradiation. NMR Biomed, 32:e4132, 2019
4. Takashima R, Ito M, Chida T, Watanabe T, Toyama T, Yaginuma T, Anzai T, Hiyama T, Iimoto T, Fujii H. EVALUATION AND STATISTICAL ANALYSIS OF THE USE OF INFOGRAPHICS IN RADIOLOGY EDUCATION. Radiat Prot Dosimetry, 184:543-546, 2019
5. Yoshii Y, Matsumoto H, Yoshimoto M, Oe Y, Zhang MR, Nagatsu K, Sugyo A, Tsuji AB, Higashi T. (64)Cu-Intraperitoneal Radioimmunotherapy: A Novel Approach for Adjuvant Treatment in a Clinically Relevant Preclinical Model of Pancreatic Cancer. J Nucl Med, 60:1437-1443, 2019
6. Hirata M, Yao T, Fujimura S, Kanai Y, Yoshimoto M, Sato T, Ohmomo Y, Temma T. Development of a p38α-selective radioactive probe for qualitative diagnosis of cancer using SPECT. Ann Nucl Med, 33:333-343, 2019
7. Yoshimoto M, Hirata M, Kagawa S, Magata Y, Ohmomo Y, Temma T. Synthesis and characterization of novel radiofluorinated probes for positron emission tomography imaging of monoamine oxidase B. J Labelled Comp Radiopharm, 62:580-587, 2019