Annual Report 2020
Division of Functional Imaging
Hirofumi Fujii, Masayuki Yamaguchi, Mitsuyoshi Yoshimoto
Introduction
Recently, therapeutic strategies to treat malignant tumors are dramatically changing. In the field of chemotherapy, many molecular targeted agents have been introduced in clinical practice and, in the field of radiotherapy, many types of particle beam therapy are used in clinical practice and some of them are also under clinical investigations. To properly perform these therapies, the evaluation of functional features of tumors including metabolism is essential. Conventional imaging tests including CT often fail to evaluate these functional aspects of tumors. To visualize them in vivo, the Division of Functional Imaging actively investigates new imaging techniques and develop epoch-making therapeutic strategies for intractable tumors.
The Team and What We Do
Our major imaging modalities include radionuclide (RN) imaging, optical imaging and magnetic resonance (MR) imaging. In the field of nuclear medicine, we are focusing on research on radionuclide therapy using alpha particles and radiotheranostics. In the field of optical imaging, we are strongly interested in imaging tests with near-infrared (NIR) light, especially NIR whose wavelength is longer than 1,000 nm, which is called OTN-NIR. In the field of MR imaging, we are actively investigating technical developments to visualize intra-tumoral perfusion and diffusion. Some experimental studies were performed using these imaging tests to develop unique imaging strategies to overcome malignant tumors.
Research activities
We are developing alpha particle radionuclide therapy for pancreatic cancer using 225Ac-labeled RGD peptide (225Ac-DOTA-RGD2) with the support of AMED Project for Cancer Research and Therapeutic Evolution. We have demonstrated that hepatotoxicity due to 225Ac-DOTA-RGD2 has been induced by free 225Ac released from chelating agents. The modification of the storage conditions improved the stability of 225Ac-DOTA-RGD2, and the administration of these modified agents significantly reduced the radioactivity due to the accumulation of alpha-emitters in the liver. Therapeutic experiments with this updated 225Ac-DOTA-RGD2 using tumor-bearing mice revealed that the growth of tumors was inhibited without showing severe side effects including weight loss and hepatotoxicity. In addition, we also investigated a method to facilitate the excretion of 225Ac accumulated from the liver and found that two chelating agents could predominantly excrete 225Ac from the liver. Our study also examines the optimization of treatment regimens.
We have been developing a novel in vivo MR imaging technique to non-invasively evaluate tumor microenvironments in collaboration with a pharmaceutical company. Our preclinical experiments on mouse models with breast cancer demonstrated that our imaging technique can evaluate blood perfusion, vascular permeability, and molecular diffusion in tumor lesions. Interestingly, by using this MR imaging technique, we successfully demonstrated that breast cancer lesions treated with a novel anticancer drug showed increased blood perfusion and vascular permeability even in formerly poorly perfused tumor tissues. This suggests that MR imaging can detect changes in blood perfusion and vascular permeability in hypoxic tumor tissues. Therefore, our MR imaging technique is thought to provide useful information on hypoxic tumors that do not respond well to conventional radiotherapy and chemotherapy.
A dual-modal imaging probe for both near-infrared fluorescence imaging and MR imaging are under investigation. We have recently found a chemical compound that can produce strong signals in both imaging modalities. It is noteworthy that our chemical compound is stable for several hours in the circulating blood without being captured by reticuloendothelial systems. Since preliminary imaging results showed promise in experimental animals, we hope that the dual-modal imaging probe would be used in clinical practice in the future.
Education
Some graduate school students took part in our studies and received doctoral or master's degrees in the 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. We are also planning to perform collaborative studies with companies so that our research results will be put to practical use.
List of papers published in 2020
Journal
1. Ohnuki K, Yoshimoto M, Fujii H. Radiological protection and biological COVID-19 protection in the nuclear medicine department. Eur J Nucl Med Mol Imaging, 48:6-8, 2021
2. Hamamichi S, Fukuhara T, Umeda IO, Fujii H, Hattori N. Novel method for screening functional antibody with comprehensive analysis of its immunoliposome. Sci Rep, 11:4625, 2021
3. 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
4. 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, 33:701-712, 2020
5. Yano T, Hasegawa K, Sato T, Tatsumi M, Watabe T, Kadonaga Y, Kabayama K, Fukase K, Hachisuka A, Hirabayashi Y, Fujii H, Yonekura Y. Rationale for translational research on targeted alpha therapy in Japan ?renaissance of radiopharmaceuticals utilizing astatine-211 and actinium-225?. RADIOISOTOPES, 69:329-340, 2020
6. Doan TKD, Umezawa M, Nigoghossian K, Yeroslavsky G, Okubo K, Kamimura M, Yamaguchi M, Fujii H, Soga K. Development of molecular imaging probe for dual NIR/MR imaging. J Photopolym Sci Technol, 33:117-122, 2020
Book
1. Morita T, Fujii H. Overview of FDG PET in Oncology in Japan. In: Fujii H, Nakamura H, Yasuda S (ed), Applications of FDG PET in Oncology -Best Clinical Practice, Singapore, Springer Singapore, pp 1-21, 2020