Research on nuclear medicine therapy
Research and development of alpha radiation nuclear medicine therapy using astatine
In Japan, there is currently intensive research being conducted on Astatine 211 (211At) and other short-lived RI with a half-life of 7 hours for nuclear medicine therapy. Collaborative efforts among Osaka University's Graduate School of Medicine, Graduate School of Science, Research Center for Nuclear Physics, and the National Institute of Radiological Sciences are at the forefront of this research and development, in partnership with venture companies. As of 2024, a investigator clinical trial is underway for thyroid cancer, utilizing a sodium astatinate drug developed through our joint research efforts. This marks the first step in testing the efficacy of this treatment at a hospital affiliated with the Faculty of Medicine. Furthermore, our team is actively engaged in the development of second and third new drugs for similar therapeutic applications. Alpha rays are high-energy helium nuclei and have the property of stopping at short distances in matter. Therefore, alpha rays emitted from astatine in a cell stop at almost one cell, destroying that cell in the process. Using this, astatine can be chemically bound (labeled) to a drug that accumulates in targeted cancer cells, and by allowing it to accumulate in the tumor after administration into the body, only the cancer cells can be efficiently destroyed. This is called alpha-ray nuclear medicine therapy, which has been under development in Europe, the United States, and Japan in recent years.
In our laboratory, we develop new labeling methods and labeled compounds for 211At, research the chemical species of 211At in the gas phase and in solution, or develop methods to produce 211At using a cyclotron accelerator.

Expansion into investigator clinical trial using astatine-labeled sodium
An investigator clinical trial aimed at treating thyroid cancer using [211At] NaAt began at Osaka University Hospital (Department of Nuclear Medicine) in December 2021, leveraging the specific uptake of astatine ion (211At-) by thyroid cancer cells. Astatine is one of the halogen elements, similar to iodine. Thyroid hormones (such as thyroxine) are biosynthesized using iodide ions (I-) as a substrate. I- is taken up into cells via the sodium iodide symporter (NIS) expressed on the thyroid cancer cell membrane. Iodine-131 (131I), a beta-emitting radionuclide, has been used for thyroid cancer treatment since the 1940s and is still considered standard therapy post-surgery. While it exhibits excellent therapeutic effects, complete cure is not always achievable, and cases of refractory thyroid cancer are not uncommon.

Start of investigator-initiated clinical trial
Similarly, At- is taken up into cells via NIS and emits alpha radiation, causing frequent double-strand breaks in DNA and killing cancer cells. When [211At] NaAt was intravenously injected into thyroid cancer model mice (0.1~1MBq), a dose-dependent inhibition of cancer growth was observed [1]. The therapeutic effect of alpha radiation is predicted to be several times to ten times higher than that of beta radiation.

The production and fundamental scientific research of astatine
Astatine is a new element discovered by Segre and others in 1940, and they foresaw its usefulness in the treatment of thyroid diseases from that time. Subsequent intermittent research has been conducted, but pharmaceuticals utilizing astatine have not yet been commercialized. One reason for this is the absence of stable isotopes of astatine, which has led to insufficient understanding of its physical and chemical properties.
Astatine is known to be chemically more prone to oxidation compared to iodine. Therefore, in our laboratory, we have successfully prepared stable astatine ions (At−) in injectable pharmaceutical-grade solutions by adding ascorbic acid to weakly basic astatine aqueous solutions. This preparation was carried out under sterile conditions and transferred to the investigational drug good manufacturing practice (GMP) facility within the hospital. The physical and chemical properties of this pharmaceutical are being thoroughly examined through various methods, including thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), mass spectrometry (LCMS, ICP-MS), electrophoresis, nuclear magnetic resonance (NMR), UV, and IR spectroscopy, combined with various radiation detectors.



Research on Astatine Labeling Basic Technology
Astatine is one of the halogen elements and can be introduced into small or medium-sized molecules via covalent bonds. In our laboratory, we have established a method for synthesizing 211At labeled compounds through the electron-deficient substitution reaction between boronic acid and astatine [2]. Figure 4 illustrates the labeling reaction of [211At] PSMA5 as an example. When a precursor (1~10µg) is treated with potassium iodide in the presence of 211At, efficient substitution of 211At occurs in aqueous solution. This reaction does not utilize any harmful substances such as organic solvents or metals, making it suitable for pharmaceutical manufacturing. [211At] PSMA5 has completed non-clinical trials as a therapeutic agent for prostate cancer [3], and first in-human investigator-initiated clinical trial started at Jun, 2024.

- [1]Watabe T, Kaneda-Nakashima K, Liu Y, Shirakami Y, Ooe K, Toyoshima A, Shimosegawa E, Fukuda M, Shinohara A, Hatazawa J. Enhancement of 211At Uptake via the Sodium Iodide Symporter by the Addition of Ascorbic Acid in Targeted α-Therapy of Thyroid Cancer J Nucl Med 2019 Sep;60(9):1301-1307. doi: 10.2967/jnumed.118.222638.
- [2]Yoshifumi Shirakami, TadashiWatabe, Honoka Obata , Kazuko Kaneda , Kazuhiro Ooe, Yuwei Liu , TakahiroTeramoto , AtsushiToyoshima , Atsushi Shinohara, Eku Shimosegawa , Jun Hatazawa, Koichi Fukase. Synthesis of [211At]4-astato-L- phenylalanine by dihydroxyboryl astatine substitution reaction in aqueous solution Scientific Reports 2021; 11:12982. doi.org/10.1038/s41598-021-92476-6
- [3]Tadashi Watabe, Kazuko Kaneda Nakashima, Yoshifumi Shirakami, Yuichiro Kadonaga, Kazuhiro Ooe, Yang Wang, Hiromitsu Haba, Asushi Toyoshima, Jens Cardinale, Frederik L. Giesel, Noriyuki Tomiyama, Koichi Fukase. Targeted α therapy using astatine 211At labeled PSMA1, 5, and 6: a preclinical evaluation as a novel compound. Eur J Nucl Med Mol Imag 2022; https://doi.org/10.1007/s00259-022-06016-z.
Research and development of beta-ray nuclear medicine therapy using scandium
In Japan, research on alpha radiation nuclear medicine therapy using 211At is being conducted at numerous universities and research institutes. Concurrently, in the field of nuclear medicine therapy using beta radiation, there is increasing global attention towards Lutetium-177 (177Lu), a short-lived RI. Overseas, beta-emitting RIs with milder effects are being used before alpha radiation nuclear medicine therapy due to safety considerations, and it is anticipated that a similar trend will occur in Japan. However, 177Lu is difficult to produce domestically as it requires the use of nuclear reactors.
Therefore, our laboratory is focusing on Scandium-47 (47Sc), a beta-emitting radioisotope that can be produced using accelerators. Its nuclear half-life, beta radiation energy, and chemical properties are similar to those of 177Lu, and we believe that it could potentially become a domestically produced beta radiation nuclear medicine therapy radioisotope in the future.
Currently, in collaboration with the Center for Electron Photon Science at Tohoku University, we are conducting research on the production method, separation and purification method, and compound labeling method of 47Sc using an electron photon accelerator. In the near future, we plan to start efficacy and pharmacology studies as well as safety testing through animal experiments in collaboration with medical and science research departments. Eventually, we envision conducting an investigator-initiated clinical trial.

Research and development of radiopharmaceuticals
In drug delivery systems used for cancer treatment and other purposes, controlling the distribution within the body to efficiently deliver drugs to lesions can maximize therapeutic effects while minimizing side effects. Currently, it is difficult to simultaneously evaluate drug accumulation and therapeutic effects without surgical intervention. However, by radiolabeling drugs (turning them into radiopharmaceuticals) and imaging the emitted gamma rays, it becomes possible to visualize drug accumulation and in vivo dynamics, offering a new tool for research.
Towards the establishment of the radiolabeling imaging system, we are conducting research on the radiolabeling and compound modification analysis of existing drugs such as cisplatin (platinum complex) and gadolinium complexes, as well as gold nanoparticles using neutrons from a nuclear reactor. Animal experiments and imaging using these radiolabeled drugs are being conducted in collaboration with the Advanced Isotope Medicine Joint Research Department and the Kataoka Laboratory at Waseda University. Imaging utilizes an innovative camera developed by the Kataoka Laboratory, which is small, high-resolution, and capable of imaging X-rays and gamma rays simultaneously over a wide energy range.

Decomission research
Research on reconstruction of the coastal region (Hamadori area) in Fukushima prefecture and decommissioning of the Fukushima Daiichi Nuclear Power Station (1F)
On March 11, 2011, the Great East Japan Earthquake struck, followed by a massive tsunami that hit the Pacific coast from the Tohoku region to the Kanto region. At the Fukushima Daiichi Nuclear Power Station (Unit 1), power sources and equipment were lost due to the tsunami, preventing the continuous cooling of the reactors. As a result, the nuclear fuel in reactors 1 to 3, which were in operation at the time, became overheated and collapsed along with surrounding structures. Additionally, certain radioactive materials such as cesium and iodine were released into the external environment, contaminating the soil mainly in Fukushima Prefecture. Fuel debris, which is solidified nuclear fuel along with structural materials, remains inside reactors 1 to 3. However, due to extremely high radiation levels, the situation assessment has not progressed satisfactorily.
Research and development of real-time monitoring method of alpha dust for decommissioning of 1F
Since the March 11, 2011 accident, efforts have been underway by the government and Tokyo Electric Power Company (TEPCO) to decommission and dismantle Unit 1 of the Fukushima Daiichi Nuclear Power Station. Among these efforts, removing the fuel debris remaining inside the reactor is considered the most challenging task. The first removal attempt is planned to be carried out experimentally in Unit 2, which did not experience a hydrogen explosion. However, the area near the removal port has high radiation levels, making it difficult for humans to approach. Therefore, various investigations are being conducted using robots and other tools.
During the removal of fuel debris, it is necessary to cut the debris into smaller pieces, which is expected to generate radioactive dust particles containing uranium and plutonium. To prevent their release into the environment, preparations are underway to connect isolation chambers to the removal ports for conducting the operations safely.
In our laboratory, in collaboration with the Toyota Laboratory at the Frontier Research Center for Applied Atomic Sciences in the Faculty of Science, we are developing new analytical methods to quickly detect generated radioactive particles and prevent their dispersion into the environment. This method utilizes an online mass analysis device called an Aerosol Time-of-Flight Mass Spectrometer (ATOFMS), which can identify the elements and molecules contained in individual particles in the air based on their mass and detect uranium and plutonium. Currently, we are conducting detection tests using simulated uranium dust created by laser ablation with the newly developed ATOFMS.
Studies on silkworms fed radioactive cesium
The coastal region (Hamadori area) in Fukushima Prefecture was severely affected by the catastrophic nuclear disaster. Gradual recovery has been achieved through decontamination efforts by the government, and evacuation orders have been gradually lifted in municipalities where they were initially issued, allowing residents to start returning. However, the scars left by forced relocation have caused significant disruption to livelihoods and industrial structures, making the process of returning arduous. Additionally, Fukushima Prefecture, originally known for its thriving agriculture, continues to suffer from the stigma of radiation contamination. Harvested crops are avoided, and prices are unfairly negotiated compared to other regions. Addressing the stigma is an urgent issue, but there is no clear solution, and the cultivation of scientific literacy seems to be the only way forward.
In this research, we aim to contribute to the recovery of Fukushima by promoting "wild silkmoth (Yamamayuga)" as a new local industry in the Hamadori area. Unfortunately, it is challenging to avoid the stigma associated with food, so we are focusing on silk, which does not involve ingestion. The silk produced by Yamamayuga is beautiful emerald green and highly valued for its excellent insulation and UV resistance. When Yamamayuga caterpillars are fed leaves contaminated with radioactive substances such as cesium, it is anticipated that the caterpillars will ingest the radioactive substances, but the dynamics of these substances within the body are not yet understood. There is a possibility that the ingested radioactive substances may be excreted through metabolism and not included in the cocoon (silk).
In this research, we aim to elucidate the internal dynamics of cesium uptake in Yamamayuga caterpillars. If radioactive substances are not present in the cocoon (silk), we can demonstrate the safety of silk products. However, if radioactive substances are found in the cocoon, we aim to establish new methods to prevent the transfer of these substances to the cocoon, thereby ensuring the safety of silk products.


