Tumor-specific delivery of BSH-3R for boron neutron capture therapy and positron emission tomography imaging in a mouse brain tumor model.
Glioblastoma, a malignant brain tumor with poor disease outcomes, is managed in modern medicine by multimodality therapy. Boron neutron capture therapy (BNCT) is an encouraging treatment under clinical investigation. In malignant cells, BNCT consists of two major factors: neutron radiation and boron uptake. To increase boron uptake in cells, we created a mercapto-closo-undecahydrododecaborate ([B12HnSH](2-)2Na(+), BSH) fused with a short arginine peptide (1R, 2R, 3R) and checked cellular uptake in vitro and in vivo. In a mouse brain tumor model, only BSH with at least three arginine domains could penetrate cell membranes of glioma cells in vitro and in vivo. Furthermore, to monitor the pharmacokinetic properties of these agents in vivo, we fused BSH and BSH-3R with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA); DOTA is a metal chelating agent for labeling positron emission tomography (PET) probe with (64)Cu. We administered BSH-DOTA-(64)Cu and BSH-3R-DOTA-(64)Cu to the tumor model through a mouse tail vein and determined the drugs' pharmacokinetics by PET imaging. BSH-3R showed a high uptake in the tumor area on PET imaging. We concluded that BSH-3R is the ideal boron compound for clinical use during BNCT and that in developing this compound for clinical use, the BSH-3R PET probe is essential for pharmacokinetic imaging.
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.
Yoshiya
Y
Iguchi
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
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 Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-Ku, Okayama City, Okayama 700-8558, Japan.
Yuri
Y
Hayashi
Collaborative Research Center for OMIC, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-Ku, Okayama City, Okayama 700-8558, Japan.
Fumiaki
F
Takenaka
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.
Hideki
H
Matsui
D000818:Animals; D001120:Arginine / Q000737:chemistry; D001895:Boron / Q000737:chemistry; D016754:Boron Neutron Capture Therapy; D001897:Boronic Acids / Q000737:chemistry*; D001932:Brain Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D002470:Cell Survival; D003300:Copper / Q000737:chemistry; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D005260:Female; D005910:Glioma / Q000532:radiotherapy; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D049268:Positron-Emission Tomography; D014057:Tomography, X-Ray Computed
D001897:Boronic Acids; D006573:Heterocyclic Compounds, 1-Ring; D009842:Oligopeptides; D010455:Peptides; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D003300:Copper; D001120:Arginine; D001895:Boron
BSH poly-arginine; Boron neutron capture therapy (BNCT); Brain tumor; CPP; DOTA; Glioma; PET; TAT