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

Number of Access:1,774（2025-07-28 20:20 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/97224

Link to primary information

File	Format	Terms of use	Size	Views	Date.Available	Description	information
IntJMolSci_25_11_5667	pdf	None	4.13 MB	102	2024.07.22

Creative Commons : Attribution

Item Information

Output File Export EndNote Basic Export Mendeley

Title	Preclinical Evaluation of Biodistribution and Toxicity of [211At]PSMA-5 in Mice and Primates for the Targeted Alpha Therapy against Prostate Cancer
Creator	NRID 1000090648932 1000090648932 ORCID 0000-0001-8658-2395 0000-0001-8658-2395 researchmap permalink twosaka2018 twosaka2018 Scopus Author ID 57421862900 57421862900 CreatorName Watabe, Tadashi
	NRID 1000000533209 1000000533209 ORCID 0000-0001-6657-5059 0000-0001-6657-5059 researchmap permalink read0131912 read0131912 CreatorName Kaneda-Nakashima, Kazuko
	NRID 1000030836903 1000030836903 researchmap permalink 3456 3456 Scopus Author ID 25928507900 25928507900 CreatorName Kadonaga, Yuichiro
	NRID 1000090610303 1000090610303 researchmap permalink 046214597 046214597 Scopus Author ID 16070507900 16070507900 CreatorName Ooe, Kazuhiro
	CreatorName Sampunta, Thosapol
	NRID 1000090830167 1000090830167 ORCID 0000-0002-3358-0916 0000-0002-3358-0916 researchmap permalink naoki-hirose naoki-hirose CreatorName Hirose, Naoki
	CreatorName Yin, Xiaojie
	NRID 1000060360624 1000060360624 CreatorName Haba, Hiromitsu
	CreatorName Kon, Yukiyoshi
	NRID 1000040414578 1000040414578 researchmap permalink read0076538 read0076538 Scopus Author ID 15833301700 15833301700 CreatorName Toyoshima, Atsushi
	CreatorName Cardinale, Jens
	CreatorName Giesel, Frederik L.
	NRID 1000080192722 1000080192722 ORCID 0000-0001-8844-0710 0000-0001-8844-0710 researchmap permalink read0076573 read0076573 Scopus Author ID 7005633724 7005633724 CreatorName Fukase, Koichi
	NRID 1000050294070 1000050294070 researchmap permalink 3430 3430 Scopus Author ID 7006024942 7006024942 CreatorName Tomiyama, Noriyuki
	NRID 1000000560400 1000000560400 researchmap permalink e5221 e5221 Scopus Author ID 6603428576 6603428576 CreatorName Shirakami, Yoshifumi
Subject	astatine
	clinical trial
	prostate cancer
	PSMA
	toxicity study
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.
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.
Publisher	Multidisciplinary Digital Publishing Institute (MDPI)
Source Title	International Journal of Molecular Sciences
Volume (Issue)	25(11)
Page	5667
Date of Issued	2024-05-23
Language	English
Handle URL	https://hdl.handle.net/11094/97224
PISSN	16616596
eISSN	14220067
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.3390/ijms25115667
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
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	English
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	English
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

Link to primary information

Item Information

Show details