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Radiat Environ Biophys. 2019 Mar;58(1):59-67. doi: 10.1007/s00411-018-0765-2. Epub 2018 Nov 24.

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

Author information

1
Department of Neurosurgery, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka, 569-8686, Japan.
2
Department of Neurosurgery, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka, 569-8686, Japan. neu046@osaka-med.ac.jp.
3
Laboratory for Chemistry and Life Science, Institute of Innovative Research Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, 226-8503, Japan.
4
Institute for Integrated Radiation and Nuclear Science, Kyoto University, 2 Asashiro-Nishi, Kumatori-cho, Sennan-gun, Osaka, 590-0494, Japan.
5
Kansai BNCT Medical Center, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka, 569-8686, Japan.
6
Section for Advanced Medical Development, Cancer Center, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka, 569-8686, Japan.

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.

KEYWORDS:

Boron neutron capture therapy; F98 glioma-bearing rat; Folate receptor; Folic acid

PMID:
30474719
DOI:
10.1007/s00411-018-0765-2

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