Abstract
AB024. Efficacy of integrin targeting novel boron carrier for boron neutron capture therapy in F98 rat glioma-bearing brain tumor models
Kohei Tsujino1, Hideki Kashiwagi1, Kai Nishimura2, Ryo Kayama1, Kohei Yoshimura1, Yusuke Fukuo1, Hiroyuki Shiba1, Ryo Hiramatsu1, Naosuke Nonoguchi1, Motomasa Furuse1, Toshihiro Takami1, Shin-Ichi Miyatake3, Naonori Hu3, Takushi Takata4, Hiroki Tanaka4, Minoru Suzuki4, Shinji Kawabata1, Hiroyuki Nakamura2, Masahiko Wanibuchi1
1Department of Neurosurgery, Osaka Medical and Pharmaceutical University, Osaka, Japan;
2Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Japan;
3Kansai BNCT Medical Center, Osaka Medical and Pharmaceutical University, Osaka, Japan;
4Institute for Integrated Radiation and Nuclear Science, Kyoto University, Osaka, Japan
Correspondence to: Shinji Kawabata, MD, PhD. Department of Neurosurgery, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki, Osaka 569-8686, Japan. Email: shinji.kawabata@ompu.ac.jp.
Background: The development of novel boron carrier is a key step in clinical boron neutron capture therapy (BNCT). We previously reported effectiveness of BNCT using maleimide-functionalized closo-dodecaborate albumin conjugate (MID-AC) in the rat brain tumor model. MID-AC is characterized by its ability to maintain intratumor boron concentration for a long time owing to the effect of albumin as the drug delivery system. However, it had the disadvantage of not having a biological tumor target at the cellular level. Therefore, cyclic arginine-glycine-aspartate-functionalized MID-AC (cRGD-MID-AC) has been developed by introducing cRGD, which targets integrin αvβ3 more highly expressed in high-grade glioma cells than in normal tissues, into MID-AC. The efficacy of BNCT using cRGD-MID-AC was evaluated.
Methods: F98 glioma cells exposed to boronophenylalanine (BPA), cRGD-MID-AC, and simple mixture of cRGD and MID were used for cellular uptake and neutron irradiation experiments. F98 glioma-bearing rat brain tumor model was used for biodistribution and neutron irradiation experiments after intravenous administration of BPA or cRGD-MID-AC.
Results: The most significant feature of cRGD-MID-AC is the high retention of cellular boron concentration owing to the tumor accumulation mechanism of albumin as well as MID-AC. In vitro neutron irradiation experiment suggested that BNCT using cRGD-MID-AC showed sufficient cell-killing effect, similar to that with BNCT using BPA. In biodistribution experiments, cRGD- MID-AC accumulated in the brain tumor, with the highest boron concentration (17.0 μg B/g) observed 8 h after administration. In the in vivo neutron irradiation experiments, Significant differences between the untreated group and BNCT using cRGD-MID-AC groups were observed through the log-rank test (P<0.05). Moreover, long-term survivors were observed in BNCT using cRGD-MID-AC for 8 h which was not observed in the other groups.
Conclusions: These findings suggest that BNCT with cRGD-MID-AC has highly selectivity for gliomas. In addition, because of different accumulation mechanisms, it might be possible to use in combination with BPA-based BNCT to make it a multi-targeted type neutron capture therapy. We believe that this long-term retention type of boron agent has many advantages in the clinical settings of BNCT, such as allowing the irradiation field to be moved during irradiation.
Keywords: Boron neutron capture therapy (BNCT); brain tumor; drug delivery system; glioma; integrin
Acknowledgments
The authors would like to acknowledge Rolf Barth (Ohio State University, Columbus, OH, USA) for providing F98 rat glioma cells. The authors also thank Aya Sunamura for her secretarial work and Itsuko Inoue for her technical assistance. This work was partly 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 K.T. and supervised by H.N.
Funding: This research was funded by the Japan Society for the Promotion of Science (JSPS) KAKENHI (No. JP20H03797 to S.K., No. JP22K09270 to Toshihiro Takami, and No. JP22K16698 to H.S.).
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tro.amegroups.com/article/view/10.21037/tro-25-ab024/coif). K.T. acknowledges receiving support from 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”. S.K., Toshihiro Takami, and H.S. declare that they received funding from JSPS KAKENHI under (Nos. JP20H03797, JP22K09270, and JP22K16698, respectively). The other authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All animal experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals and were approved by both the Animal Use Review Board and Ethical Committee of Osaka Medical and Pharmaceutical University (approval No. 21085-A) and the Institute for Integrated Radiation and Nuclear Science, Kyoto University (KURNS; Kumatori, Osaka, Japan) (approval No. 2021-18).
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the noncommercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
doi: 10.21037/tro-25-ab024
Cite this abstract as: Tsujino K, Kashiwagi H, Nishimura K, Kayama R, Yoshimura K, Fukuo Y, Shiba H, Hiramatsu R, Nonoguchi N, Furuse M, Takami T, Miyatake SI, Hu N, Takata T, Tanaka H, Suzuki M, Kawabata S, Nakamura H, Wanibuchi M. AB024. Efficacy of integrin targeting novel boron carrier for boron neutron capture therapy in F98 rat glioma-bearing brain tumor models. Ther Radiol Oncol 2025;9:AB024.
