Annual Report 2021
Division of Functional Imaging
Hirofumi Fujii, Masayuki Yamaguchi, Mitsuyoshi Yoshimoto, Doan Thi Kim Dung
Introduction
Recently, therapeutic strategies for malignant tumors have been changing dramatically. New types of anticancer drugs such molecular targeted agents and immune-checkpoint inhibitors and particle beam therapy have been introduced in clinical practice. To properly perform these therapies, the evaluation of functional features of tumors such as metabolism is essential. Conventional morphological imaging tests such as 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 develops 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. Additionally, radiation protection issues are also under investigation. In the field of optical imaging, we are highly 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
In the study of radionuclide therapy and radiotheranostics, we have been developing alpha particle radionuclide therapy for pancreatic cancer using 225Ac-labeled RGD peptide (225Ac-DOTA-RGD2) with the support of the AMED Project for Cancer Research and Therapeutic Evolution. We previously discovered that DOTA-RGD2 could show strong specific affinity to pancreatic tumor cells, which often show high expression of integrin. In the therapeutic study using mouse tumor models, 225Ac-DOTA-RGD2 dose-dependently inhibited tumor growth. In experiments using tumor cells, 225Ac-DOTA-RGD2 also strongly inhibited the cell growth. The IC50s correlated well with the uptake of 111In-DOTA-RGD2 in tumor cells. We also confirmed a dose-dependent increase in the expression of γH2AX, which is an indicator of DNA double-strand breaks. These results indicated that 225Ac-DOTA-RGD2 would be a promising therapeutic agent against pancreatic cancer.
Although radionuclide therapy using 225Ac is promising, it is not easy to constantly obtain this alpha emitter because we currently get almost all of it from foreign countries. To resolve this problem, we started a collaboration with a company to produce 225Ac using accelerators in Japan and obtained promising initial results.
Radiation protection is another important issue especially when alpha particle emitters are used. We discovered that 211At, which is another promising alpha particle emitter and is highly volatile, easily passed through the polyethylene-coated filter paper that is commonly used to protect against contamination due to disseminated radionuclides. To overcome this problem, we examined materials that can block the infiltration of 211At and investigated combinations of adsorbents and plastic sheets with high gas-barrier properties. We found that a combination of activated carbon and a polychlorovinylidene sheet was useful for sealing in the vapor and solution of 211At.
In the study of magnetic resonance imaging (MRI), we have been developing a novel MR imaging technique to non-invasively evaluate tumor microenvironments in collaboration with a pharmaceutical company and the University of Tsukuba. Preclinical experiments on breast cancer mouse models demonstrated that a dynamic contrast-enhanced MR imaging technique can semi-quantitatively evaluate blood perfusion and vascular permeability in tumor lesions. Moreover, we have developed new software that can clearly display temporal changes of tumor microenvironments related to perfusion inside tumors by using a clustering technique. Interestingly, breast cancer lesions showed an increase in blood perfusion and vascular permeability during the course of treatment using a novel anticancer drug, which is expected to induce vascular remodeling, and eventually decrease the tumor size. We hypothesize that the vascular remodeling effects of this anti-tumor agent might have enhanced anti-cancer effects.Further investigation is underway to clarify this idea.
A dual-modal imaging probe for both near-infrared fluorescence imaging and MR imaging are under investigation in collaboration with Tokyo University of Science. We synthesized a chemical compound that can produce strong signals in both imaging modalities. We performed further experiments to test the functional properties of the probe in conjunction with anti-HER2 antibodies. We hope this probe may be clinically applicable in the future for breast cancer diagnosis and treatment.
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. 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 2021
Journal
1. Doan TKD, Umezawa M, Ohnuki K, Nigoghossian K, Okubo K, Kamimura M, Yamaguchi M, Fujii H, Soga K. The influence of Gd-DOTA conjugating ratios to PLGA-PEG micelles encapsulated IR-1061 on bimodal over-1000 nm near-infrared fluorescence and magnetic resonance imaging. Biomaterials science, 10:1217-1230, 2022
2. Yamaguchi M, Kojo K, Akatsuka M, Haishi T, Kobayashi T, Nakajima T, Nishiyama H, Fujii H. High Resolution MR Imaging of the Testis Using a Small Radiofrequency Coil. Magnetic resonance in medical sciences: MRMS: an official journal of Japan Society of Magnetic Resonance in Medicine, 2022
3. Yagishita A, Takeda S, Katsuragawa M, Kawamura T, Matsumura H, Orita T, Umeda IO, Yabu G, Caradonna P, Takahashi T, Watanabe S, Kanayama Y, Mizuma H, Ohnuki K, Fujii H. Simultaneous visualization of multiple radionuclides in vivo. Nature biomedical engineering, 6:640-647, 2022
4. Sagara H, Inoue K, Yaku H, Ohsawa A, Someya T, Yanagisawa K, Ohashi S, Ishigaki R, Wakabayashi M, Muramatsu Y, Fujii H. Optimization of injection dose in 18F-FDG PET/CT based on the 2020 national diagnostic reference levels for nuclear medicine in Japan. Annals of nuclear medicine, 35:1177-1186, 2021
5. Takashima H, Koga Y, Manabe S, Ohnuki K, Tsumura R, Anzai T, Iwata N, Wang Y, Yokokita T, Komori Y, Mori D, Usuda S, Haba H, Fujii H, Matsumura Y, Yasunaga M. Radioimmunotherapy with an 211 At-labeled anti-tissue factor antibody protected by sodium ascorbate. Cancer science, 112:1975-1986, 2021
6. Manabe S, Takashima H, Ohnuki K, Koga Y, Tsumura R, Iwata N, Wang Y, Yokokita T, Komori Y, Usuda S, Mori D, Haba H, Fujii H, Yasunaga M, Matsumura Y. Stabilization of an 211At-Labeled Antibody with Sodium Ascorbate. ACS omega, 6:14887-14895, 2021
7. Suzuki H, Kise S, Kaizuka Y, Watanabe R, Sugawa T, Furukawa T, Fujii H, Uehara T. Copper-64-Labeled Antibody Fragments for Immuno-PET/Radioimmunotherapy with Low Renal Radioactivity Levels and Amplified Tumor-Kidney Ratios. ACS omega, 6:21556-21562, 2021
8. Yoshimoto M, Yoshii Y, Matsumoto H, Shinada M, Takahashi M, Igarashi C, Hihara F, Tachibana T, Doi A, Higashi T, Fujii H, Washiyama K. Evaluation of Aminopolycarboxylate Chelators for Whole-Body Clearance of Free (225)Ac: A Feasibility Study to Reduce Unexpected Radiation Exposure during Targeted Alpha Therapy. Pharmaceutics, 13:2021