Annual Report 2018
Division of Functional Imaging
Hirofumi Fujii, Izumi O. Umeda, 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
We introduced alpha-emitters in our RN laboratory this fiscal year and started experiments of RN therapies using alpha-emitters such as At-211 and Ac-225, which have attracted considerable attention among researchers in the oncology field given the fact that the linear energy transfer of these alpha nuclides is sufficient to irreparably break down double strands of DNA, independent of oxygen concentration, as part of successful treatment for intractable cancer. We focused on folate receptors that are highly expressed in certain malignancies such as ovarian cancer. We also synthesized a folate derivative, which was successfully labeled with At-211 using a tin-precursor. Our experiments about the biodistribution of the compounds obtained, which was labeled with I-125, instead of At-211, revealed that our current radioactive agent was insufficient to treat intractable cancer successfully. Since these markedly accumulated in the liver and intestine without showing an excellent affinity to tumors at the early postinjection phase, we are now synthesizing new folate analogs with low lipophilicity.
We also started collaborating with other research groups within and outside our research institutes towards ensuring the safe and effective clinical application of alpha emitters.
We have been engaged in investigating radiotheranostics using liposomal agents and have already successfully encapsulated In-111, a representative diagnostic RN, in liposomes using remote loading methods and clearly imaged tumors. Currently, we have been trying to develop an efficient method to encapsulate radioactive cupper such as Cu-64, a representative therapeutic RN, in liposomes. Stable cationic Cu2+ ions could be encapsulated in liposomes by remote loading and the formation of chelate complex of cationic Cu2+ ions and chelating ligands in aqueous phase inside liposomes was validated by HPLC. High loading efficiency, which exceeded 90%, was obtained by incubation at over 40°C for as short as 30 min. The biodistribution and tumor accumulation of obtained Cu-64-carrying liposomes were evaluated using Sarcoma180-bearing mice. Tumor accumulation was as good as 8-9 %AD/g for each liposome, which was quite similar to In- 111-EC liposomes and no Cu-64 was dissociated from the ligands. These results suggested that our RN-carrying liposomes could be promising radiotheranostics agents.
As for magnetic resonance imaging (MRI) studies, we have been developing novel diagnostic imaging applications utilizing an ultrahigh-field 9.4 tesla scanner that may assist efforts to deliver cancer therapy safely and effectively. The visualization of treatment margins surrounding hepatic tumors in radiotherapy using MRI is one of our standout research achievements. As we previously reported, the irradiated liver areas (i.e. treatment margin) and tumors can be clearly contrasted on MR images when contrast media known as superparamagnetic iron-oxide nanoparticles (SPIONs) are systemically administered before a clinical dose of X-irradiation was applied to the liver of rats. We also found that the irradiated liver area looked dark owing to the accumulation of SPIONs in resident macrophages, called Kupffer cells, which were damaged by x-irradiation. This year, we conducted in vitro experiments to elucidate the mechanism of the SPIONs accumulation in the damaged macrophages and found for the first time that x-irradiation could slow the degradation process to SPIONs in the macrophages. We hope the technique will soon become popular in clinical practice and help radiation oncologists realize that ionizing radiation indeed hits the target tumor and treatment margin in the liver as they planned.
Education
Some graduate school students took part in our studies and received doctoral or master degrees in fields of medicine and related sciences.
Future prospects
We will develop our research projects to translate our research products into clinical practice.
List of papers published in 2018
Journal
1. Yoshii Y, Matsumoto H, Yoshimoto M, Oe Y, Zhang MR, Nagatsu K, Sugyo A, Tsuji AB, Higashi T. 64Cu-intraperitoneal radioimmunotherapy: a novel approach for adjuvant treatment in a clinically relevant preclinical model of pancreatic cancer. J Nucl Med, 2019
2. Tsuchimochi M, Yamaguchi H, Hayama K, Okada Y, Kawase T, Suzuki T, Tsubokawa N, Wada N, Ochiai A, Fujii S, Fujii H. Imaging of Metastatic Cancer Cells in Sentinel Lymph Nodes using Affibody Probes and Possibility of a Theranostic Approach. Int J Mol Sci, 20:2019
3. Iimoto T, Fujii H, Someya S, Matsuzawa H, Yanagawa Y, Kunii K. Cooperation process between a local government and experts in official voluntary decontamination of environmental radioactivity. J Radiat Res, 59:ii48-ii53, 2018
4. Yoshimoto M, Honda N, Kurihara H, Hiroi K, Nakamura S, Ito M, Shikano N, Itami J, Fujii H. Non-invasive estimation of 10B-4-borono- L-phenylalanine-derived boron concentration in tumors by PET using 4-borono-2-18F-fluoro-phenylalanine. Cancer Sci, 109:1617-1626, 2018
5. Yamaguchi M, Fujii H. Immobilization Technique for High-Resolution MR Imaging of the Testes. Magn Reson Med Sci, 17:338- 343, 2018
6. Yoshii Y, Yoshimoto M, Matsumoto H, Tashima H, Iwao Y, Takuwa H, Yoshida E, Wakizaka H, Yamaya T, Zhang MR, Sugyo A, Hanadate S, Tsuji AB, Higashi T. Integrated treatment using intraperitoneal radioimmunotherapy and positron emission tomography- guided surgery with 64Cu-labeled cetuximab to treat early- and late-phase peritoneal dissemination in human gastrointestinal cancer xenografts. Oncotarget, 9:28935-28950, 2018
Book
1. Ohnuki K, Fujii H. Nonclinical imaging studies for the diagnosis of lymph node metastases. In: Natsugoe S (ed), Lymph node metastasis in gastrointestinal cancer, Singapore, Springer Singapore, pp 127-157, 2019