Annual Report 2017
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, radiotheranostics, the integration of diagnostic procedures and therapeutic strategies, is an important research topic and we are investigating radiotheranostics using liposomes encapsulating radionuclides. A major problem in radiotheranostics using liposomes is physiological retention of radionuclides in reticuloendothelial tissues such as the liver and spleen. Our idea to overcome this problem is to establish the method to rapidly excrete radionuclides or radioactive ligands from reticuloendothelial tissues after they accumulated in reticuloendothelial tissues. We have developed unique radiolabeled ligands for diagnostic purpose and we also disclosed the difference of the speed of excretion of radioactivity from reticuloendothelial tissues among animal models. We started the study to synthesize ligands that show high affinity to therapeutic radionuclides in addition to diagnostic ones.
We also used liposomes as tools for the evaluation of characteristics of tumor angiogenesis and revealed the difference between tumor vessels induced by VEGF and those by FGF.
Nuclear medicine therapy using alpha nuclides is currently attracting strong attention because linear energy transfer of alpha nuclides is high enough to irreparably break double strand of DNA, independent of oxygen concentration. Among alpha nuclides, 225Ac is popular one since it can be used to label peptides and antibodies via chelating agents such as DOTA. We previously reported that 111In-DOTA-c(RGDfK) clearly depicted small lesions of pancreatic and lung cancers in carcinogenesis animal models. We aimed to develop radionuclide therapy using 225Ac-labelled RGD peptide (225Ac-DOTA-E[c(RGDfK)]2). We suc-cessfully purified 225Ac from 229Th using UTEVA and DGA resin. Labelling of DOTA-E[c(RGDfK)]2 with 225Ac was successfully carried out and the labelling yield was about 60 %.
In the field of magnetic resonance (MR) imaging, we have developed a novel method to concurrently display the irradiated liver parenchyma and liver tumor on a single MR image. Our preclinical experiments demonstrate that the irradiated liver areas and tumors can be clearly contrasted on MR images when a contrast media, called superparamagnetic iron-oxide nanoparticles (SPIONs), is systemically administered before irradiation. Since both MR imaging and SPIONs are clinically available, we hope the techniques become popular soon in clinical practice, and help radiation oncologists to realize that ionizing radiation indeed hits the target tumor and treatment margin in the liver as they planned. In addition, we have developed another novel technique to visualize the seminiferous tubules on MR images. The key technologies are an extremely high sensitive signal detector, called a radiofrequency (RF) coil, to increase the signal from the micron-sized tubules and an immobilization technique of the testis during MR examinations to avoid motion artifacts. We tested a dedicated RF coil and negative pressure suction in combination and eventually succeeded in the observation of seminiferous tubules non-invasively in vivo. We believe that the technique would support andrologists and urologists to treat male cancer survivors with infertility caused by chemotherapy and radiotherapy in their childhood.
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.
List of papers published in January 2017 - March 2018
Journal
1. Furuta T, Yamaguchi M, Minami M, Ohtomo K, Fujii H. Persistent T2*-hypointensity of the liver parenchyma after irradiation to the SPIO-accumulated liver: An imaging marker for responses to radiotherapy in hepatic malignancies. J Magn Reson Imaging, 45:303-312, 2017
2. Kagawa S, Nishii R, Higashi T, Yamauchi H, Ogawa E, Okudaira H, Kobayashi M, Yoshimoto M, Shikano N, Kawai K. Relationship between [14C]MeAIB uptake and amino acid transporter family gene expression levels or proliferative activity in a pilot study in human carcinoma cells: Comparison with [3H]methionine uptake. Nucl Med Biol, 49:8-15, 2017
3. Yoshii Y, Yoshimoto M, Matsumoto H, Furukawa T, Zhang MR, Inubushi M, Tsuji AB, Fujibayashi Y, Higashi T, Saga T. 64Cu-ATSM internal radiotherapy to treat tumors with bevacizumab-induced vascular decrease and hypoxia in human colon carcinoma xenografts. Oncotarget, 8:88815-88826, 2017
4. Hori Y, Ito K, Hamamichi S, Ozawa Y, Matsui J, Umeda IO, Fujii H. Functional Characterization of VEGF- and FGF-induced Tumor Blood Vessel Models in Human Cancer Xenografts. Anticancer Res, 37:6629-6638, 2017
5. Ito K, Hamamichi S, Abe T, Akagi T, Shirota H, Kawano S, Asano M, Asano O, Yokoi A, Matsui J, Umeda IO, Fujii H. Antitumor effects of eribulin depend on modulation of the tumor microenvironment by vascular remodeling in mouse models. Cancer Sci, 108:2273-2280, 2017
6. Kano D, Nakagami Y, Kurihara H, Hosokawa S, Zenda S, Kusumoto M, Fujii H, Kaneta T, Saito S, Uesawa Y, Kagaya H. Development of a double-stranded siRNA labelling method by using 99mTc and single photon emission computed tomography imaging. J Drug Target, 25:172-178, 2017
7. Yoshii Y, Matsumoto H, Yoshimoto M, Zhang MR, Oe Y, Kurihara H, Narita Y, Jin ZH, Tsuji AB, Yoshinaga K, Fujibayashi Y, Higashi T. Multiple Administrations of 64Cu-ATSM as a Novel Therapeutic Option for Glioblastoma: a Translational Study Using Mice with Xenografts. Transl Oncol, 11:24-30, 2018