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Development of probes for radiotheranostics with albumin binding moiety to increase the therapeutic effects of astatine-211 (211At)

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Abstract

Purpose

We have developed probes for multiradionuclides radiotheranostics using RGD peptide ([67Ga]Ga-DOTA-c[RGDf(4-I)K] ([67Ga]1) and Ga-DOTA-[211At]c[RGDf(4-At)K] ([211At]2)) for clinical applications. The introduction of an albumin binding moiety (ABM), such as 4-(4-iodophenyl)-butyric acid (IPBA), that has high affinity with the blood albumin and prolongs the circulation half-life can improve the pharmacokinetics of drugs. To perform more effective targeted alpha therapy (TAT), we designed and synthesized Ga-DOTA-K([211At]APBA)-c(RGDfK) ([211At]5) with 4-(4-astatophenyl)-butyric acid (APBA), which has an astato group instead of an iodo group in IPBA. We evaluated whether APBA functions as ABM and [211At]5 is effective for TAT. In addition, we prepared 67Ga-labeled RGD peptide without ABM, [67Ga]Ga-DOTA-K-c(RGDfK) ([67Ga]3), and 125I-labeled RGD peptide with ABM, Ga-DOTA-K([125I]IPBA)-c(RGDfK) ([125I]4), to compare with [211At]5.

Methods

Biodistribution experiments of [67Ga]3 without ABM, [125I]4 and [211At]5 with ABM were conducted in normal mice and U-87 MG tumor-bearing mice. In addition, two doses of [211At]5 (370 or 925 kBq) were administered to U-87 MG tumor-bearing mice to confirm the therapeutic effects.

Results

The blood retention of [125I]4 and [211At]5 was remarkably increased compared to [67Ga]3. Also, [125I]4 and [211At]5 showed similar biodistribution and significantly greater tumor accumulation and retention compared to [67Ga]3. In addition, [211At]5 inhibited tumor growth in a dose-dependent manner.

Conclusion

The functionality of APBA as ABM like IPBA, and the usefulness of [211At]5 as the radionuclide therapy agent for TAT was revealed.

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Data availability

Data are available from the corresponding author on reasonable request.

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Funding

This work was supported in part by Grants-in-Aid for Scientific Research (21H02867) from the Ministry of Education, Culture, Sports, Science and Technology, Japan, The Mitani Foundation for Research and Development, the Program of the Network-type Joint Usage/Research Center for Radiation Disaster Medical Science, and JST SPRING (JPMJSP2135).

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Authors and Affiliations

  1. Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, 920-1192, Japan

    Hiroaki Echigo, Masayuki Munekane, Takeshi Fuchigami & Kazuma Ogawa

  2. Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, 920-1192, Japan

    Kenji Mishiro & Kazuma Ogawa

  3. Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan

    Kohshin Washiyama & Kazuhiro Takahashi

  4. Research Center for Experimental Modeling of Human Disease, Kanazawa University, Takara-machi 13-1, Kanazawa, Ishikawa, 920-8640, Japan

    Yoji Kitamura

  5. Department of Nuclear Medicine, Kanazawa University Hospital, Kanazawa University, Takara-machi 13-1, Kanazawa, Ishikawa, 920-8641, Japan

    Hiroshi Wakabayashi & Seigo Kinuya

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  1. Hiroaki Echigo
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Contributions

Conceptualization: Hiroaki Echigo and Kazuma Ogawa. Methodology: Hiroaki Echigo, Kenji Mishiro, Masayuki Munekane, Takeshi Fuchigami, and Kazuma Ogawa. Analysis: Hiroaki Echigo, Kenji Mishiro, and Kazuma Ogawa. Writing — original draft preparation: Hiroaki Echigo and Kazuma Ogawa. Writing — review and editing: Kenji Mishiro, Masayuki Munekane, Takeshi Fuchigami, and Kazuma Ogawa. Funding acquisition: Kazuma Ogawa. Resources: Kohshin Washiyama, Kazuhiro Takahashi, Yoji Kitamura, Hiroshi Wakabayashi, and Seigo Kinuya. Supervision: Kenji Mishiro and Kazuma Ogawa. All authors commented on previous versions of the manuscript and approved the final manuscript.

Corresponding author

Correspondence to Kazuma Ogawa.

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The authors have no conflict of interest.

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Experiments with animals were conducted in strict accordance with the Guidelines for the Care and Use of Laboratory Animals of Kanazawa University. The experimental protocols were approved by the Committee on Animal Experimentation of Kanazawa University. This article does not contain any studies with human participants performed by any of the authors.

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Echigo, H., Mishiro, K., Munekane, M. et al. Development of probes for radiotheranostics with albumin binding moiety to increase the therapeutic effects of astatine-211 (211At). Eur J Nucl Med Mol Imaging 51, 412–421 (2024). https://doi.org/10.1007/s00259-023-06457-0

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