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Folate receptor-targeted novel boron compound for boron neutron capture therapy on F98 glioma-bearing rats

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Abstract

Folic acid (FA) has high affinity for the folate receptor (FR), which is limited expressed in normal human tissues, but over-expressed in several tumor cells, including glioblastoma cells. In the present work, a novel pteroyl–closo-dodecaborate conjugate (PBC) was developed, in which the pteroyl group interacts with FR, and the efficacy of boron neutron capture therapy (BNCT) using PBC was investigated. Thus, in vitro and in vivo studies were performed using F98 rat glioma cells and F98 glioma-bearing rats. For the in vivo study, boronophenylalanine (BPA) was intravenously administered, while PBC was administered by convection-enhanced delivery (CED)—a method for direct local drug infusion into the brain of rats. Furthermore, a combination of PBC administered by CED and BPA administered by intravenous (i.v.) injection was also investigated. In the biodistribution experiment, PBC administration at 6 h after CED termination showed the highest cellular boron concentrations (64.6 ± 29.6 µg B/g). Median survival time (MST) of untreated controls was 23.0 days (range 21–24 days). MST of rats administered PBC (CED) followed by neutron irradiation was 31 days (range 26–36 days), which was similar to that of rats administered i.v. BPA (30 days; range 25–37 days). Moreover, the combination group [PBC (CED) and i.v. BPA] showed the longest MST (38 days; range 28–40 days). It is concluded that a significant MST increase was noted in the survival time of the combination group of PBC (CED) and i.v. BPA compared to that in the single-boron agent groups. These findings suggest that the combination use of PBC (CED) has additional effects.

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Acknowledgements

This work was performed under the Research Program for Next Generation Young Scientists of “Dynamic Alliance for Open Innovation Bridging Human, Environment and Materials” in “Network Joint Research Center for Materials and Devices” with funds for T.K. supervised by H.N. The authors thank Dr. Barth (Department of Pathology, the Ohio State University, Columbus, OH, US) for providing the F98 rat glioma cells. The authors would like to thank Enago (http://www.enago.jp) for the English language review. This study was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI Grant number JP17K10878 to S.K. [Grants-in-Aid for Scientific Research (C)] and Grant number JP17K16666 to R.H. [Grants-in-Aid for Young Scientists (B)].

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Authors and Affiliations

  1. Department of Neurosurgery, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka, 569-8686, Japan

    Takuya Kanemitsu, Shinji Kawabata, Masao Fukumura, Gen Futamura, Ryo Hiramatsu, Naosuke Nonoguchi & Toshihiko Kuroiwa

  2. Laboratory for Chemistry and Life Science, Institute of Innovative Research Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, 226-8503, Japan

    Fumiko Nakagawa & Hiroyuki Nakamura

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

    Takushi Takata, Hiroki Tanaka, Minoru Suzuki & Shin-Ichiro Masunaga

  4. Kansai BNCT Medical Center, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka, 569-8686, Japan

    Koji Ono

  5. Section for Advanced Medical Development, Cancer Center, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka, 569-8686, Japan

    Shin-Ichi Miyatake

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  1. Takuya Kanemitsu
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  2. Shinji Kawabata
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  3. Masao Fukumura
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  4. Gen Futamura
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  5. Ryo Hiramatsu
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  6. Naosuke Nonoguchi
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  7. Fumiko Nakagawa
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  8. Takushi Takata
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  9. Hiroki Tanaka
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  10. Minoru Suzuki
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  11. Shin-Ichiro Masunaga
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  12. Koji Ono
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  13. Shin-Ichi Miyatake
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  14. Hiroyuki Nakamura
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  15. Toshihiko Kuroiwa
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Correspondence to Shinji Kawabata.

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All procedures were performed in accordance with the guide for the care and use of laboratory animals as approved by the Animal Use Review Board and Ethical Committee of Osaka Medical College and Kyoto University Research Reactor Institute (KURRI; Kumatori, Osaka, Japan).

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Kanemitsu, T., Kawabata, S., Fukumura, M. et al. Folate receptor-targeted novel boron compound for boron neutron capture therapy on F98 glioma-bearing rats. Radiat Environ Biophys 58, 59–67 (2019). https://doi.org/10.1007/s00411-018-0765-2

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  • DOI: https://doi.org/10.1007/s00411-018-0765-2

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