The acceleration of boron neutron capture therapy using multi-linked mercaptoundecahydrododecaborate (BSH) fused cell-penetrating peptide.
New anti-cancer therapy with boron neutron capture therapy (BNCT) is based on the nuclear reaction of boron-10 with neutron irradiation. The median survival of BNCT patients with glioblastoma was almost twice as long as those receiving standard therapy in a Japanese BNCT clinical trial. In this clinical trial, two boron compounds, BPA (boronophenylalanine) and BSH (sodium borocaptate), were used for BNCT. BPA is taken up into cells through amino acid transporters that are expressed highly in almost all malignant cells, but BSH cannot pass through the cell membrane and remains outside the cell. We simulated the energy transfer against the nucleus at different locations of boron from outside the cell to the nuclear region with neutron irradiation and concluded that there was a marked difference between inside and outside the cell in boron localization. To overcome this disadvantage of BSH in BNCT, we used a cell-penetrating peptide system for transduction of BSH. CPP (cell-membrane penetrating peptide) is very common peptide domains that transduce many physiologically active substances into cells in vitro and in vivo. BSH-fused CPPs can penetrate the cell membrane and localize inside a cell. To increase the boron ratio in one BSH-peptide molecule, 8BSH fused to 11R with a dendritic lysine structure was synthesized and administrated to malignant glioma cells and a brain tumor mouse model. 8BSH-11R localized at the cell nucleus and showed a very high boron value in ICP results. With neutron irradiation, the 8BSH-11R administrated group showed a significant cancer killing effect compared to the 100 times higher concentration of BSH-administrated group. We concluded that BSH-fused CPPs were one of the most improved and potential boron compounds in the next-stage BNCT trial and 8BSH-11R may be applied in the clinical setting.
Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-Ku, Okayama City, Okayama 700-8558, Japan. Electronic address: hmichiue@md.okayama-u.ac.jp.
Hiroyuki
H
Michiue
Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, Kumatori-cho, Osaka 590-0494, Japan.
Yoshinori
Y
Sakurai
Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, Kumatori-cho, Osaka 590-0494, Japan.
Natsuko
N
Kondo
Department of Applied Chemistry, Faculty of Science and Engineering, Kinki University, 3-4-1 Kowakae, Higashi-Osaka City, Osaka 577-8502, Japan.
Mizuki
M
Kitamatsu
Department of Biotechnology, Dalian Medical University, No. 9 West Section, Lvshun South, Dalian 116044, China.
Feng
F
Bin
KNC Laboratories, Ltd., 1-1-1, Murotani, Nishi-ku, Kobe City, Hyogo 651-2241, Japan.
Kiichiro
K
Nakajima
Department of Neurosurgery, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japan.
Yuki
Y
Hirota
Department of Neurosurgery, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japan.
Shinji
S
Kawabata
Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-Ku, Okayama City, Okayama 700-8558, Japan.
Tei-ichi
T
Nishiki
Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-Ku, Okayama City, Okayama 700-8558, Japan.
Iori
I
Ohmori
Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjou, Kumamoto City, Kumamoto 860-8556, Japan.
Kazuhito
K
Tomizawa
Department of Neurosurgery, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japan.
Shin-ichi
S
Miyatake
Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, Kumatori-cho, Osaka 590-0494, Japan.
Koji
K
Ono
Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-Ku, Okayama City, Okayama 700-8558, Japan.
Hideki
H
Matsui
D001894:Borohydrides / Q000627:therapeutic use*; D016754:Boron Neutron Capture Therapy; D001932:Brain Neoplasms / Q000532:radiotherapy; D005909:Glioblastoma / Q000532:radiotherapy; D006801:Humans; D010455:Peptides / Q000627:therapeutic use*; D013438:Sulfhydryl Compounds / Q000627:therapeutic use*
D001894:Borohydrides; D010455:Peptides; D013438:Sulfhydryl Compounds; C014651:mercaptoundecahydrododecaborate
BSH poly-arginine; Oron neutron capture therapy (BNCT); Protein transduction; TAT