α‐Methyl‐l‐tyrosine (AMT) has a high affinity for the cancer‐specific l‐type amino acid transporter 1 (LAT1). Therefore, we established an anti‐cancer therapy, with ²¹¹At‐labeled α‐methyl‐l‐tyrosine (²¹¹At‐AAMT) as a carrier of ²¹¹At into tumors. ²¹¹At‐AAMT had high affinity for LAT1, inhibited tumor cell growth, and induced DNA double‐stranded breaks in vitro. We evaluated the accumulation of ²¹¹At‐AAMT in vivo and the role of LAT1. Treatment with 0.4 MBq/mouse ²¹¹At‐AAMT inhibited tumor growth in the PANC‐1 tumor model and 1 MBq/mouse ²¹¹At‐AAMT inhibited metastasis in the lung of the B16F10 metastasis model. Our results suggested that ²¹¹At would be useful for anti‐cancer therapy and that LAT1 is suitable as a target for radionuclide therapy.

Alpha-particle radiotherapy has gained considerable attention owing to its potent anti-cancer effect. ²¹¹At, with a relatively short half-life of 7.2 h, emits an alpha particle within a few cell diameters with high kinetic energy, which damages cancer cells with high biological effectiveness. In this study, we investigated the intravenous injection of ²¹¹At-labeled gold nanoparticles (AuNPs) for targeted alpha-particle therapy (TAT). Different kinds of surface-modified gold nanoparticles can be labeled with ²¹¹At in high radiochemical yield in 5 min, and no purification is necessary. The in vivo biodistribution results showed the accumulation of 5 nm ²¹¹At-AuNPs@mPEG at 2.25% injection dose per gram (% ID/g) in tumors within 3 h via the enhanced permeability and retention (EPR) effect. Additionally, we observed a long retention time in tumor tissues within 24 h. This is the first study to demonstrate the anti-tumor efficacy of 5 nm ²¹¹At-AuNPs@mPEG that can significantly suppress tumor growth in a pancreatic cancer model via intravenous administration. AuNPs are satisfactory carriers for ²¹¹At delivery, due to simple and efficient synthesis processes and high stability. The intravenous administration of 5 nm ²¹¹At-AuNPs@mPEG has a significant anti-tumor effect. This study provides a new framework for designing nanoparticles suitable for targeted alpha-particle therapy via intravenous injection.

Astatine (²¹¹At) is an alpha-emitter with a better treatment efficacy against differentiated thyroid cancer compared with iodine (¹³¹I), a conventional beta-emitter. However, its therapeutic comparison has not been fully evaluated. In this study, we compared the therapeutic effect between [²¹¹At]NaAt and [¹³¹I]NaI. In vitro analysis of a double-stranded DNA break (DSB) and colony formation assay were performed using K1-NIS cells. The therapeutic effect was compared using K1-NIS xenograft mice administered with [²¹¹At]NaAt (0.4 MBq (n = 7), 0.8 MBq (n = 9), and 1.2 MBq (n = 4)), and [¹³¹I]NaI (1 MBq (n = 4), 3 MBq (n = 4), and 8 MBq (n = 4)). The [²¹¹At]NaAt induced higher numbers of DSBs and had a more reduced colony formation than [¹³¹I]NaI. In K1-NIS mice, dose-dependent therapeutic effects were observed in both [²¹¹At]NaAt and [¹³¹I]NaI. In [²¹¹At]NaAt, a stronger tumour-growth suppression was observed, while tumour regrowth was not observed until 18, 25, and 46 days after injection of 0.4, 0.8, and 1.2 MBq of [²¹¹At]NaAt, respectively. While in [¹³¹I]NaI, this was observed within 12 days after injection (1, 3, and 8 MBq). The superior therapeutic effect of [²¹¹At]NaAt suggests the promising clinical applicability of targeted alpha therapy using [²¹¹At]NaAt in patients with differentiated thyroid cancer refractory to standard [¹³¹I]NaI treatment.

Fibroblast activation proteins (FAP) are overexpressed in the tumor stroma and have received attention as target molecules for radionuclide therapy. The FAP inhibitor (FAPI) is used as a probe to deliver nuclides to cancer tissues. In this study, we designed and synthesized four novel ²¹¹At-FAPI(s) possessing polyethylene glycol (PEG) linkers between the FAP-targeting and ²¹¹At-attaching moieties. ²¹¹At-FAPI(s) and piperazine (PIP) linker FAPI exhibited distinct FAP selectivity and uptake in FAPII-overexpressing HEK293 cells and the lung cancer cell line A549. The complexity of the PEG linker did not significantly affect selectivity. The efficiencies of both linkers were almost the same. Comparing the two nuclides, ²¹¹At was superior to ¹³¹I in tumor accumulation. In the mouse model, the antitumor effects of the PEG and PIP linkers were almost the same. Most of the currently synthesized FAPI(s) contain PIP linkers; however, in our study, we found that PEG linkers exhibit equivalent performance. If the PIP linker is inconvenient, a PEG linker is expected to be an alternative.

Astatine (²¹¹At) is a cyclotron-produced alpha emitter with a physical half-life of 7.2 h. In our previous study, the ²¹¹At-labeled prostate-specific membrane antigen (PSMA) compound ([²¹¹At]PSMA-5) exhibited excellent tumor growth suppression in a xenograft model. We conducted preclinical biodistribution and toxicity studies for the first-in-human clinical trial. [²¹¹At]PSMA-5 was administered to both normal male ICR mice (n = 85) and cynomolgus monkeys (n = 2). The mice were divided into four groups for the toxicity study: 5 MBq/kg, 12 MBq/kg, 35 MBq/kg, and vehicle control, with follow-ups at 1 day (n = 10 per group) and 14 days (n = 5 per group). Monkeys were observed 24 h post-administration of [²¹¹At]PSMA-5 (9 MBq/kg). Blood tests and histopathological examinations were performed at the end of the observation period. Blood tests in mice indicated no significant myelosuppression or renal dysfunction. However, the monkeys displayed mild leukopenia 24 h post-administration. Despite the high accumulation in the kidneys and thyroid, histological analysis revealed no abnormalities. On day 1, dose-dependent single-cell necrosis/apoptosis was observed in the salivary glands of mice and intestinal tracts of both mice and monkeys. Additionally, tingible body macrophages in the spleen and lymph nodes indicated phagocytosis of apoptotic B lymphocytes. Cortical lymphopenia (2/10) in the thymus and a decrease in the bone marrow cells (9/10) were observed in the 35 MBq/kg group in mice. These changes were transient, with no irreversible toxicity observed in mice 14 days post-administration. This study identified no severe toxicities associated with [²¹¹At]PSMA-5, highlighting its potential as a next-generation targeted alpha therapy for prostate cancer. The sustainable production of ²¹¹At using a cyclotron supports its applicability for clinical use.

Background: L-type amino acid transporter 1 (LAT1) is overexpressed in various cancers; therefore, radiohalogen-labeled amino acid derivatives targeting LAT1 have emerged as promising candidates for cancer radiotheranostics. However, ²¹¹At-labeled amino acid derivatives exhibit instability against deastatination in vivo, making it challenging to use ²¹¹At for radiotherapy. In this study, radiohalogen-labeled amino acid derivatives with high dehalogenation stability were developed. Results: We designed and synthesized new radiohalogen-labeled amino acid derivatives ([²¹¹At]At-NpGT, [¹²⁵I]I-NpGT, and [¹⁸F]F-NpGT) in which L-tyrosine was introduced into the neopentyl glycol (NpG) structure. The radiolabeled amino acid derivatives were recognized as substrates of LAT1 in the in vitro studies using C6 glioma cells. In a biodistribution study using C6 glioma-bearing mice, these agents exhibited high stability against in vivo dehalogenation and similar biodistributions. The similarity of [²¹¹At]At-NpGT and [¹⁸F]F-NpGT indicated that these pairs of radiolabeled compounds would be helpful in radiotheranostics. Moreover, [²¹¹At]At-NpGT exhibited a dose-dependent inhibitory effect on the growth of C6 glioma-bearing mice. Conclusions: [²¹¹At]At-NpGT exhibited a dose-dependent inhibitory effect on the tumor growth of glioma-bearing mice, and its biodistribution was similar to that of other radiohalogen-labeled amino acid derivatives. These findings suggest that radiotheranostics using [¹⁸F]F-NpGT and [^123/131I]I-NpGT for diagnostic applications and [²¹¹At]At-NpGT and [¹³¹I]I-NpGT for therapeutic applications are promising.