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Abstract

Evaluation of the Safety of Folate Receptor-Targeted Boron Carrier in Boron Neutron Capture Therapy (BNCT) for Malignant Gliomas Using CED Administration †

1
Department of Neurosurgery, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan
2
Institute for Integrated Radiation and Nuclear Science, Kyoto University, Kumatori 520-2113, Japan
3
Kansai BNCT Medical Center, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan
4
Department of Radiation Oncology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
5
Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama 226-8503, Japan
*
Author to whom correspondence should be addressed.
Presented at the 4th International Electronic Conference on Cancers, 6–8 March 2024; Available online: https://sciforum.net/event/IECC2024.
Proceedings 2024, 100(1), 15; https://doi.org/10.3390/proceedings2024100015
Published: 27 March 2024
(This article belongs to the Proceedings of The 4th International Electronic Conference on Cancers)

1. Introduction

Knowing how to accumulate boron into the tumor cells is a crucial aspect of boron neutron capture therapy (BNCT), which can be targeted at the cellular level, and the development of novel boron agents other than BPA, which is used in clinical practice, is urgently needed. Our previous work demonstrated the efficacy of BNCT in malignant gliomas using PBC-IP, a pteroyl-closo-dodecaborate-conjugated 4-(p-iodophenyl) butyric acid with folate receptor targeting. Administered through convection-enhanced delivery (CED), PBC-IP resulted in long-term survival equivalent to cure, surpassing BPA outcomes. While the local administration method has been employed for the treatment of brain tumors using this drug, its applicability extends to cancers in other organs throughout the body through intravenous administration. Consequently, this report emphasizes the safety of BNCT treatment with this drug, examining both local dosing in the brain and intravenous administration in the experimental investigation. This study focuses on assessing PBC-IP’s safety in CED procedures and implications for clinical application.

2. Methods

PBC-IP was administered intravenously or via CED to normal Fischer rats. At the predetermined time, each organ was collected and boron concentration was measured via Inductively Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES). The intravenous administration of PBC-IP aimed to evaluate toxicity in cases where the tip of the CED catheter was implanted in the normal brain or accidentally inserted into a blood vessel. Additionally, CED administration of PBC-IP to normal rats aimed to evaluate the extent of drug clearance from normal tissues. PBC-IP concentrations were set at a maximum of 5000 μg B/mL for intravenous administration and 1500 μg B/mL for CED.

3. Results

Upon PBC-IP administration intravenously, no indications of apparent toxicity were observed in post-administration assessments. Furthermore, the boron concentration in each organ was within acceptable limits. The maximum boron concentration was 10.3 ± 0.8 μg B/g in the liver at a dose of 200 μL of PBC-IP 5000 μg B/mL. The boron concentration in the brain on the same side as PBC-IP CED administration exhibited a gradual decrease, while boron concentrations in other organs were minimal (the boron concentrations in each organ were less than 1 μg B/g).

4. Conclusions

Safety assessments revealed no apparent toxicity with intravenous administration, and acceptable boron concentrations in organs. CED administration exhibited gradual brain boron reduction, minimizing concentrations in other organs. Furthermore, the potential of BNCT with intravenous administration of this drug for cancers in organs other than the brain has been explored, and the safety of the drug in such scenarios has been established. PBC-IP emerges as a non-toxic, swiftly cleared boron agent, offering promise for BNCT applications. Future clinical prospects are encouraging, positioning PBC-IP as a potential breakthrough in boron neutron capture therapy.

Author Contributions

Conceptualization, K.N. (Kei Nakai), H.N. and S.K.; methodology, K.T., H.K., R.K., Y.F. (Yusuke Fukuo) and R.H.; formal analysis, investigation and data curation, K.T., H.K., T.T. and H.T.; resources, K.T., H.K., K.N. (Kai Nishimura), Y.F. (Yoshiki Fujikawa), R.K., R.H., T.T. and H.T.; writing—original draft preparation, K.T., H.K. and N.H.; writing—review and editing, H.T., N.H. and S.K.; supervision, N.N., M.S. and M.W.; project administration and funding acquisition, H.N. and S.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by 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. supervised by H.N., the Japan Society for the Promotion of Science (JSPS) KAKENHI (Grants-in-Aid for Science Research [B]) under Grant Number JP23H03024 to S.K., and AMED under Grant Numbers JP20cm0106262 and JP23ym0126070 to H.N., K.N. and S.K.

Institutional Review Board Statement

The study was conducted in accordance with the guidelines of the Declaration of Helsinki and approved by the Animal Use Review Board and Ethical Committee of Osaka Medical and Pharmaceutical University (No. AM23-060) and the Institute for Integrated Radiation and Nuclear Science, Kyoto University (KURNS; Kumatori, Osaka, Japan) (No. R5031).

Informed Consent Statement

Not applicable.

Data Availability Statement

The datasets analyzed in the current study are available from the corresponding author upon reasonable request. The JMP Pro version 16.2.0. software(SAS, Cary, NC, USA) was used for statistical analysis.

Conflicts of Interest

All authors declare that they have no conflicts of interests.
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Share and Cite

MDPI and ACS Style

Tsujino, K.; Kashiwagi, H.; Kayama, R.; Fujikawa, Y.; Fukuo, Y.; Hiramatsu, R.; Nonoguchi, N.; Takata, T.; Tanaka, H.; Suzuki, M.; et al. Evaluation of the Safety of Folate Receptor-Targeted Boron Carrier in Boron Neutron Capture Therapy (BNCT) for Malignant Gliomas Using CED Administration. Proceedings 2024, 100, 15. https://doi.org/10.3390/proceedings2024100015

AMA Style

Tsujino K, Kashiwagi H, Kayama R, Fujikawa Y, Fukuo Y, Hiramatsu R, Nonoguchi N, Takata T, Tanaka H, Suzuki M, et al. Evaluation of the Safety of Folate Receptor-Targeted Boron Carrier in Boron Neutron Capture Therapy (BNCT) for Malignant Gliomas Using CED Administration. Proceedings. 2024; 100(1):15. https://doi.org/10.3390/proceedings2024100015

Chicago/Turabian Style

Tsujino, Kohei, Hideki Kashiwagi, Ryo Kayama, Yoshiki Fujikawa, Yusuke Fukuo, Ryo Hiramatsu, Naosuke Nonoguchi, Takushi Takata, Hiroki Tanaka, Minoru Suzuki, and et al. 2024. "Evaluation of the Safety of Folate Receptor-Targeted Boron Carrier in Boron Neutron Capture Therapy (BNCT) for Malignant Gliomas Using CED Administration" Proceedings 100, no. 1: 15. https://doi.org/10.3390/proceedings2024100015

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