Improved Boron Neutron Capture Therapy Using Integrin αvβ3-Targeted Long-Retention-Type Boron Carrier in a F98 Rat Glioma Model
Kohei Tsujino, Hideki Kashiwagi, Kai Nishimura, Ryo Kayama, Kohei Yoshimura, Yusuke Fukuo, Hiroyuki Shiba, Ryo Hiramatsu, Naosuke Nonoguchi, Motomasa Furuse, Toshihiro Takami, Shin‐Ichi Miyatake, Naonori Hu, Takushi Takata, Hiroki Tanaka, Minoru Suzuki, Shinji Kawabata, Hiroyuki Nakamura, Masahiko Wanibuchi
Abstract
Integrin αvβ3 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 αvβ3 was developed. The efficacy of boron neutron capture therapy (BNCT) targeting integrin αvβ3 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.