Preclinical Evaluation of Biodistribution and Toxicity of [211At]PSMA-5 in Mice and Primates for the Targeted Alpha Therapy against Prostate Cancer

Watabe, Tadashi; Kaneda-Nakashima, Kazuko; Kadonaga, Yuichiro; Ooe, Kazuhiro; Sampunta, Thosapol; Hirose, Naoki; Yin, Xiaojie; Haba, Hiromitsu; Kon, Yukiyoshi; Toyoshima, Atsushi; Cardinale, Jens; Giesel, Frederik L.; Fukase, Koichi; Tomiyama, Noriyuki; Shirakami, Yoshifumi

doi:https://doi.org/10.3390/ijms25115667

Preclinical Evaluation of Biodistribution and Toxicity of [211At]PSMA-5 in Mice and Primates for the Targeted Alpha Therapy against Prostate Cancer

Watabe, Tadashi; Kaneda-Nakashima, Kazuko; Kadonaga, Yuichiro et al.

International Journal of Molecular Sciences, 2024, 25(11), 5667

アクセス数:65件（2025-04-17 23:26 集計）

固定URL: https://hdl.handle.net/11094/97224

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タイトル	Preclinical Evaluation of Biodistribution and Toxicity of [211At]PSMA-5 in Mice and Primates for the Targeted Alpha Therapy against Prostate Cancer
著者	NRID 1000090648932 1000090648932 ORCID 0000-0001-8658-2395 0000-0001-8658-2395 researchmap permalink twosaka2018 twosaka2018 Scopus Author ID 57421862900 57421862900 著者名 Watabe, Tadashi
	NRID 1000000533209 1000000533209 ORCID 0000-0001-6657-5059 0000-0001-6657-5059 researchmap permalink read0131912 read0131912 著者名 Kaneda-Nakashima, Kazuko
	NRID 1000030836903 1000030836903 researchmap permalink 3456 3456 Scopus Author ID 25928507900 25928507900 著者名 Kadonaga, Yuichiro
	NRID 1000090610303 1000090610303 researchmap permalink 046214597 046214597 Scopus Author ID 16070507900 16070507900 著者名 Ooe, Kazuhiro
	著者名 Sampunta, Thosapol
	NRID 1000090830167 1000090830167 ORCID 0000-0002-3358-0916 0000-0002-3358-0916 researchmap permalink naoki-hirose naoki-hirose 著者名 Hirose, Naoki
	著者名 Yin, Xiaojie
	NRID 1000060360624 1000060360624 著者名 Haba, Hiromitsu
	著者名 Kon, Yukiyoshi
	NRID 1000040414578 1000040414578 researchmap permalink read0076538 read0076538 Scopus Author ID 15833301700 15833301700 著者名 Toyoshima, Atsushi
	著者名 Cardinale, Jens
	著者名 Giesel, Frederik L.
	NRID 1000080192722 1000080192722 ORCID 0000-0001-8844-0710 0000-0001-8844-0710 researchmap permalink read0076573 read0076573 Scopus Author ID 7005633724 7005633724 著者名 Fukase, Koichi
	NRID 1000050294070 1000050294070 researchmap permalink 3430 3430 Scopus Author ID 7006024942 7006024942 著者名 Tomiyama, Noriyuki
	NRID 1000000560400 1000000560400 researchmap permalink e5221 e5221 Scopus Author ID 6603428576 6603428576 著者名 Shirakami, Yoshifumi
キーワード等	astatine
	clinical trial
	prostate cancer
	PSMA
	toxicity study
内容	Watabe T., Kaneda-Nakashima K., Kadonaga Y., et al. Preclinical Evaluation of Biodistribution and Toxicity of [211At]PSMA-5 in Mice and Primates for the Targeted Alpha Therapy against Prostate Cancer. International Journal of Molecular Sciences 25, 5667 (2024); https://doi.org/10.3390/ijms25115667.
抄録	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.
出版者	Multidisciplinary Digital Publishing Institute (MDPI)
収録物名	International Journal of Molecular Sciences
巻(号)	25(11)
ページ	5667
刊行年月	2024-05-23
言語	英語
ハンドルURL	https://hdl.handle.net/11094/97224
PISSN	16616596
eISSN	14220067
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.3390/ijms25115667
アクセス権	open access
権利情報	This article is licensed under a Creative Commons Attribution 4.0 International License.
出版タイプ	Version of Record
カテゴリ	学術雑誌論文 Journal Article

資源タイプ	学術雑誌論文
ローカル資源タイプ	学術雑誌論文
DCTERMS.bibliographicCitation	International Journal of Molecular Sciences. 2024, 25(11), p. 5667
DC.title	Preclinical Evaluation of Biodistribution and Toxicity of [211At]PSMA-5 in Mice and Primates for the Targeted Alpha Therapy against Prostate Cancer
DC.creator	Watabe, Tadashi
	Kaneda-Nakashima, Kazuko
	Kadonaga, Yuichiro
	Ooe, Kazuhiro
	Sampunta, Thosapol
	Hirose, Naoki
	Yin, Xiaojie
	Haba, Hiromitsu
	Kon, Yukiyoshi
	Toyoshima, Atsushi
	Cardinale, Jens
	Giesel, Frederik L.
	Fukase, Koichi
	Tomiyama, Noriyuki
	Shirakami, Yoshifumi
DC.publisher	Multidisciplinary Digital Publishing Institute (MDPI)
DC.language' scheme='DCTERMS.RFC1766	英語
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2024-05-23
DC.identifier	https://doi.org/10.3390/ijms25115667
DC.subject	astatine
	clinical trial
	prostate cancer
	PSMA
	toxicity study
DC.description	Watabe T., Kaneda-Nakashima K., Kadonaga Y., et al. Preclinical Evaluation of Biodistribution and Toxicity of [211At]PSMA-5 in Mice and Primates for the Targeted Alpha Therapy against Prostate Cancer. International Journal of Molecular Sciences 25, 5667 (2024); https://doi.org/10.3390/ijms25115667.
DCTERMS.abstract	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.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	97224
citation_title	Preclinical Evaluation of Biodistribution and Toxicity of [211At]PSMA-5 in Mice and Primates for the Targeted Alpha Therapy against Prostate Cancer
citation_author	Watabe, Tadashi
	Kaneda-Nakashima, Kazuko
	Kadonaga, Yuichiro
	Ooe, Kazuhiro
	Sampunta, Thosapol
	Hirose, Naoki
	Yin, Xiaojie
	Haba, Hiromitsu
	Kon, Yukiyoshi
	Toyoshima, Atsushi
	Cardinale, Jens
	Giesel, Frederik L.
	Fukase, Koichi
	Tomiyama, Noriyuki
	Shirakami, Yoshifumi
citation_publisher	Multidisciplinary Digital Publishing Institute (MDPI)
citation_language	英語
citation_date	2024-05-23
citation_journal_title	International Journal of Molecular Sciences
citation_volume	25
citation_issue	11
citation_firstpage	5667
citation_doi	https://doi.org/10.3390/ijms25115667
citation_public_url	https://hdl.handle.net/11094/97224

Preclinical Evaluation of Biodistribution and Toxicity of [211At]PSMA-5 in Mice and Primates for the Targeted Alpha Therapy against Prostate Cancer

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