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Improved Boron Neutron Capture Therapy Using Integrin αvβ3-Targeted Long-Retention-Type Boron Carrier in a F98 Rat Glioma Model

SIMPLE SUMMARY: The development of a novel boron carrier is a key step in clinical boron neutron capture therapy (BNCT). We previously reported that maleimide-functionalized closo-dodecaborate albumin conjugate (MID-AC) with albumin as the drug delivery system is an effective boron carrier for the F...

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Detalles Bibliográficos
Autores principales: Tsujino, Kohei, Kashiwagi, Hideki, Nishimura, Kai, Kayama, Ryo, Yoshimura, Kohei, Fukuo, Yusuke, Shiba, Hiroyuki, Hiramatsu, Ryo, Nonoguchi, Naosuke, Furuse, Motomasa, Takami, Toshihiro, Miyatake, Shin-Ichi, Hu, Naonori, Takata, Takushi, Tanaka, Hiroki, Suzuki, Minoru, Kawabata, Shinji, Nakamura, Hiroyuki, Wanibuchi, Masahiko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10045558/
https://www.ncbi.nlm.nih.gov/pubmed/36979069
http://dx.doi.org/10.3390/biology12030377
Descripción
Sumario:SIMPLE SUMMARY: The development of a novel boron carrier is a key step in clinical boron neutron capture therapy (BNCT). We previously reported that maleimide-functionalized closo-dodecaborate albumin conjugate (MID-AC) with albumin as the drug delivery system is an effective boron carrier for the F98 glioma-bearing rat brain tumor model. In this study, the efficacy of BNCT with cRGD-MID-AC, a cyclic arginine-glycine-aspartate (cRGD) targeting integrin α(v)β(3) added to MID-AC, was evaluated in a glioma-bearing rat brain tumor model. Although the cellular boron concentration of cRGD-MID-AC was lower than that of boronophenylalanine (BPA), in vitro neutron-irradiation experiments confirmed that the cell-killing effect of BNCT using cRGD-MID-AC was similar to that of BNCT using BPA. In vivo biodistribution showed a sufficient boron concentration in the tumor after intravenous administration. In neutron-irradiation experiments, the BNCT group using cRGD-MID-AC showed significantly prolonged survival compared to the untreated group, and long-term survivors were observed. This drug shows promise as a novel agent for BNCT. ABSTRACT: Integrin α(v)β(3) is more highly expressed in high-grade glioma cells than in normal tissues. In this study, a novel boron-10 carrier containing maleimide-functionalized closo-dodecaborate (MID), serum albumin as a drug delivery system, and cyclic arginine-glycine-aspartate (cRGD) that can target integrin α(v)β(3) was developed. The efficacy of boron neutron capture therapy (BNCT) targeting integrin α(v)β(3) in glioma cells in the brain of rats using a cRGD-functionalized MID-albumin conjugate (cRGD-MID-AC) was evaluated. F98 glioma cells exposed to boronophenylalanine (BPA), cRGD-MID-AC, and cRGD + MID were used for cellular uptake and neutron-irradiation experiments. An F98 glioma-bearing rat brain tumor model was used for biodistribution and neutron-irradiation experiments after BPA or cRGD-MID-AC administration. BNCT using cRGD-MID-AC had a sufficient cell-killing effect in vitro, similar to that with BNCT using BPA. In biodistribution experiments, cRGD-MID-AC accumulated in the brain tumor, with the highest boron concentration observed 8 h after administration. Significant differences were observed between the untreated group and BNCT using cRGD-MID-AC groups in the in vivo neutron-irradiation experiments through the log-rank test. Long-term survivors were observed only in BNCT using cRGD-MID-AC groups 8 h after intravenous administration. These findings suggest that BNCT with cRGD-MID-AC is highly selective against gliomas through a mechanism that is different from that of BNCT with BPA.