Masashi Murakami

Targeted alpha therapy is generally evaluated by absorbed dose and direct tumor-cell killing, but whether alpha-particle–injured tumor cells can induce systemic antitumor immunity remains poorly defined. We investigated the immunogenic consequences of astatine-211 (²¹¹At) injury in a prophylactic melanoma vaccination–challenge model. B16F10 cells were exposed ex vivo to ²¹¹At, etoposide, or ultraviolet irradiation under conditions that reduced viable-cell counts at 24 hours to approximately 40% of untreated controls. Injured cells were administered subcutaneously to syngeneic C57BL/6J mice before intravenous challenge with viable B16F10 cells. Vaccination with cells exposed to 1 MBq/mL ²¹¹At suppressed pulmonary metastasis, reduced regulatory T-cell proportions, and elicited tumor-reactive interferon-γ responses and antibodies. Transcriptomic profiling revealed enrichment of type I interferon, inflammatory, and chemokine-related signatures, together with suppression of cell-cycle, translation, and metabolic programs. At the cellular level, ²¹¹At injury was accompanied by γH2AX accumulation, G2/M arrest, increased reactive oxygen species and cytosolic double-stranded DNA, and senescence-like changes. These features arose without consistent increases in classical damage-associated molecular patterns or prominent induction of senescence-associated secretory phenotype factors at 1 MBq/mL. In vivo pharmacologic inhibition of stimulator of interferon genes (STING) signaling attenuated the antimetastatic effect of vaccination. Together, these findings demonstrate that ²¹¹At injury can generate an immunostimulatory tumor-cell state characterized by DNA damage and altered inflammatory signaling. STING contributes to the resulting immune protection, highlighting immunogenic tumor-cell conversion as a consideration in the design of targeted alpha therapies.

Neurotensin receptor 1 (NTSR1) is overexpressed in various types of cancer and known as a promising target for cancer therapy. Targeted alpha therapy (TAT) using α-emitting radionuclides with high linear energy transfer is expected to show potent therapeutic efficacy. In this study, we aimed to develop an 211At-labeled NTSR1-TAT agent. To achieve this, [125I]IB-NTS, [125I]IB-DOTA-NTS, and [125I]IB-In-DOTA-NTS were newly designed, synthesized, and evaluated using 125I as a surrogate radionuclide. These 125I-labeled compounds showed high stability in murine plasma and NTSR1-binding affinity. In the biodistribution study, [125I]IB-In-DOTA-NTS demonstrated the most favorable tumor uptake among the three compounds and in vivo NTSR1-specificity. Therefore, [211At]AB-In-DOTA-NTS was synthesized and its utility as an NTSR1-TAT agent was evaluated. [211At]AB-In-DOTA-NTS exhibited dose-dependent antitumor effects without sustained or dose-dependent body weight loss in HT-29 tumor-bearing mice. This study demonstrated that [211At]AB-In-DOTA-NTS is a promising candidate for TAT and represents the first report of an 211At-labeled NTSR1-TAT agent.

Background/Objectives: Peritoneal dissemination of malignancies leads to poor prognoses, and no effective treatment currently exists. The difficulty of treating such malignancies is likely because systemically administered drugs cannot easily target malignant cells in the abdominal cavity. High intraperitoneal drug retention, non-toxicity towards normal tissues, and successful targeting of malignant cells are important for an effective therapy. The aim of this study was to evaluate an intraperitoneally administered astatine-labeled, integrin-targeted nanodrug, mPEG(Mn:350)-S-AuNP[²¹¹At]-c[RGDfK(C)] ([²¹¹At]AuNP@PEG/RGD), with respect to its kinetics, therapeutic efficacy, and safety. Methods: C6 rat glioma cells (10⁷), and BxPC3 (10⁷) and PANC-1 (10⁷) human pancreatic cancer cells were seeded intraperitoneally into nude mice, and [²¹¹At]AuNP@PEG/RGD (0.979 ± 0.194 MBq for C6 models (n = 3), 1.139 ± 0.035 MBq for BxPC3 models (n = 10), and 1.308 ± 0.039 MBq for PANC-1 models (n = 10) per mouse) or saline were intraperitoneally administered 4–7 days later. Cytotoxicity against malignant cells, pharmacokinetics after administration, therapeutic efficacy, and safety in abdominal organs were evaluated. Results: Intraperitoneally administered [²¹¹At]AuNP@PEG/RGD accumulated exclusively in the peritoneal cavity for a long period of time and showed minimal systemic diffusion through the blood. In the C6 model, the intraperitoneal tumor mass was significantly lower in the treated group compared with that of the controls (p = 0.05). For the BxPC3 (median survival time: control/treated = 41/65 days, p < 0.001) and PANC-1 (median survival time: control/treated = 19/35 days, p < 0.001) peritoneal dissemination models, survival analysis revealed that [²¹¹At]AuNP@PEG/RGD significantly prolonged overall survival. Although transient weight loss, leukopenia, and thrombocytopenia were observed at one week post-administration, a short recovery trend was evident thereafter. One month after administration, no abnormalities were found in hematological tests or histological analyses of intra-abdominal organs. Conclusions: The intraperitoneal administration of astatine-labeled integrin-targeted [²¹¹At]AuNP@PEG/RGD nanoparticles showed promising findings in terms of safety and efficacy for treating peritoneally disseminated malignant tumors.

This study investigated the distribution and dispersion of Sc-47 (⁴⁷Sc), a β-emitting radionuclide that can be produced in large quantities using accelerators. As the stability of labeled compounds inside the body is essential for nuclear medicine therapy, we examined the biodistribution of free ⁴⁷Sc to distinguish it from the distribution of compounds labeled with ⁴⁷Sc. [⁴⁷Sc]ScCl₃ was administered to normal mice. Body distribution, excretion routes, and contamination of laboratory equipment were also measured. ⁴⁷Sc remained in the blood for long periods and accumulated mainly in the liver and kidneys because of its binding to plasma proteins. Therefore, ⁴⁷Sc released from the labeled compounds could potentially cause non-specific liver and kidney damage. Most of the ⁴⁷Sc was eliminated through feces, whereas some was excreted through the urinary system. ⁴⁷Sc was found in both the liquid and solid components of the blood. Although animal cages were contaminated with excreta, they could be effectively cleaned by wiping with paper. We also used ⁴⁷Sc produced by us to label PSMA-617 and verified its performance as a nuclear medicine therapeutic agent. Although [⁴⁷Sc]Sc-PSMA-617 did not exhibit a high accumulation rate in tumors, it demonstrated antitumor activity. This might suggest the usefulness of ⁴⁷Sc.

In nuclear medicine, there is a growing demand for imaging the pharmacokinetics of various therapeutic drugs. Although there are promising radiopharmaceuticals that emit gamma rays of several hundred keV, imaging devices offering high contrast and spatial resolution in this energy range have not yet been developed. Compton cameras perform imaging in high-energy regions, including several hundred keV and even higher than MeV; however, their spatial resolution is relatively low. Single-photon emission computed tomography (SPECT) offers high spatial resolution for imaging with X-rays and gamma rays below 200 keV. However, thick collimator walls are required for imaging in high-energy regions, leading to limited statistics and low image contrast. Therefore, we developed a high-contrast SPECT (HC-SPECT) system capable of high-contrast and high-resolution imaging using gamma rays in a several hundred keV range. We developed a collimator with an array of hourglass-shaped holes that efficiently collect gamma rays while maintaining the thickness of the collimator walls to prevent noise events. In this study, a prototype HC-SPECT system was developed, and its performance was compared with that of a Compton camera and parallel-hole SPECT.

Amyloid-β (Aβ) aggregates are one of the pathological hallmarks and also an important therapeutic target of Alzheimer's disease (AD). Although targeted alpha therapy (TAT) has been established primarily for cancer treatments, it has potential application as a novel treatment approach for AD by reducing Aβ aggregates. However, no TAT agents targeting Aβ aggregates have demonstrated usefulness in vivo. In this study, we newly synthesized and evaluated [211At]APBF-2, a pyridyl benzofuran (PBF) derivative labeled with astatine-211 (211At, t1/2 = 7.2 h), as a small molecule-based TAT agent targeting Aβ aggregates. In an in vitro thioflavin T (ThT) assay, [211At]APBF-2 significantly reduced the quantity of Aβ1-42 aggregates. Additionally, in an in vivo biodistribution study using normal mice, [211At]APBF-2 demonstrated favorable blood-brain barrier (BBB) permeability (2.95% injected dose (ID)/g at 2 min after intravenous injection). These results suggest that [211At]APBF-2 may be a TAT agent demonstrating therapeutic efficacy against AD in vivo.

We investigated nuclear medicine therapeutics targeting the L-type amino acid transporter 1 (LAT1). We previously reported that a nuclear medicine therapeutic drug using astatine 211 (²¹¹At), an alpha-emitting nuclide that can be produced in an accelerator and targets LAT1 as a molecular target, is effective. The seed compound was 3-[²¹¹At] Astato-α-methyl-L-tyrosine (²¹¹At-AAMT-OH-L). We used a unique labeling method. By changing the OH group of phenol to a methyl group, retention was successfully increased. It was also found that the amount of the L-isomer taken up by the D-isomer and L-isomer was clearly higher, and the L-isomer was superior as a therapeutic drug. Compounds in which the methyl group was replaced with an ethyl or propyl group were also examined, but their retention did not increase significantly. In fact, we observed increased non-specific accumulation and dynamics, suggesting that labeling may be off. In addition, ²¹¹At-AAMT-O-Me-L, which has a simple structure, was clearly superior in terms of uptake speed for several candidate compounds. As a result, we were able to develop a compound that can be easily labeled, has high specific radioactivity, is stable, and has a strong therapeutic effect.