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Pharmacokinetic Study of 14C-Radiolabeled p-Boronophenylalanine (BPA) in Sorbitol Solution and the Treatment Outcome of BPA-Based Boron Neutron Capture Therapy on a Tumor-Bearing Mouse Model

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objective

Boron neutron capture therapy (BNCT) is a binary cancer treatment that combines boron administration and neutron irradiation. The tumor cells take up the boron compound and the subsequent neutron irradiation results in a nuclear fission reaction caused by the neutron capture reaction of the boron nuclei. This produces highly cytocidal heavy particles, leading to the destruction of tumor cells. p-boronophenylalanine (BPA) is widely used in BNCT but is insoluble in water and requires reducing sugar or sugar alcohol as a dissolvent to create an aqueous solution for administration. The purpose of this study was to investigate the pharmacokinetics of 14C-radiolabeled BPA using sorbitol as a dissolvent, which has not been reported before, and confirm whether neutron irradiation with a sorbitol solution of BPA can produce an antitumor effect of BNCT.

Materials and Methods

In this study, we evaluated the sugar alcohol, sorbitol, as a novel dissolution aid and examined the consequent stability of the BPA for long-term storage. U-87 MG and SAS tumor cell lines were used for in vitro and in vivo experiments. We examined the pharmacokinetics of 14C-radiolabeled BPA in sorbitol solution, administered either intravenously or subcutaneously to a mouse tumor model. Neutron irradiation was performed in conjunction with the administration of BPA in sorbitol solution using the same tumor cell lines both in vitro and in vivo.

Results

We found that BPA in sorbitol solution maintains stability for longer than in fructose solution, and can therefore be stored for a longer period. Pharmacokinetic studies with 14C-radiolabeled BPA confirmed that the sorbitol solution of BPA distributed through tumors in much the same way as BPA in fructose. Neutron irradiation was found to produce dose-dependent antitumor effects, both in vitro and in vivo, after the administration of BPA in sorbitol solution.

Conclusion

In this report, we demonstrate the efficacy of BPA in sorbitol solution as the boron source in BNCT.

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Authors and Affiliations

  1. Institute for Integrated Radiation and Nuclear Science, Kyoto University, 2, Asashiro-Nishi, Kumatori-cho, Sennan-gun, Osaka, 590-0494, Japan

    Tsubasa Watanabe, Hiroki Tanaka, Yuko Kinashi, Shin-ichiro Masunaga, Koji Ono & Minoru Suzuki

  2. The Hakubi Project, Kyoto University, Kyoto, Japan

    Tsubasa Watanabe

  3. Stella Pharma Corporation, Osaka, Japan

    Tomohiro Yoshikawa, Toshimitsu Hayashi & Koki Uehara

  4. Radioisotope Research Center, Nara Medical University, Nara, Japan

    Genro Kashino

  5. Kinshukai Hanwa Daini Senboku Hospital, Osaka, Japan

    Shin-ichiro Masunaga

  6. Kansai BNCT Medical Center, Osaka Medical and Pharmaceutical University, Osaka, Japan

    Koji Ono

Authors
  1. Tsubasa Watanabe
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  2. Tomohiro Yoshikawa
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  3. Hiroki Tanaka
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  4. Yuko Kinashi
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  5. Genro Kashino
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  6. Shin-ichiro Masunaga
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  7. Toshimitsu Hayashi
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  8. Koki Uehara
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  9. Koji Ono
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  10. Minoru Suzuki
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Corresponding authors

Correspondence to Tsubasa Watanabe or Minoru Suzuki.

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Funding

No funding was received for this work.

Conflict of interest

Three of the authors (T.Y., T.H., and K.U.) declare conflicts of interest based on their relationships with Stella Pharma Corporation. The remaining authors have no conflicts of interest to declare.

Availability of data and materials

The raw data before analysis can be downloaded as supplementary data in this manuscript.

Code availability

Not applicable. No special codes were used in the analysis of this study’s data.

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Not applicable.

Consent for publication

Not applicable.

Author contributions

K.O., T.H., and K.U. conceived and designed the study. T.Y., H.T., Y.K., G.K., S.-I. M., and S. M. performed experiments and data analyses. T.W. performed additional data analyses. K.O., and S. M. supervised the project. T.W., T.H., and K.U. wrote the manuscript. All authors edited and approved the manuscript.

Ethics approval

The mice used in this study were cared for and treated according to the Recommendations for the Handling of Laboratory Animals for Biomedical Research by the Committee on Ethical Handling Regulations for Laboratory Animal Experiments, Kyoto University. Additionally, all animal experiments were approved by Ethical Handling Regulations for Laboratory Animal Experiments, Kyoto University (approval no. 200813) and conducted per the laboratory animal handling guidelines of our institution.

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Watanabe, T., Yoshikawa, T., Tanaka, H. et al. Pharmacokinetic Study of 14C-Radiolabeled p-Boronophenylalanine (BPA) in Sorbitol Solution and the Treatment Outcome of BPA-Based Boron Neutron Capture Therapy on a Tumor-Bearing Mouse Model. Eur J Drug Metab Pharmacokinet 48, 443–453 (2023). https://doi.org/10.1007/s13318-023-00830-y

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