Tumor-specific delivery of BSH-3R for boron neutron capture therapy and positron emission tomography imaging in a mouse brain tumor model

• Published in: Biomaterials Vol. 56; pp. 10 - 17
• Main Authors: Iguchi, Yoshiya, Michiue, Hiroyuki, Kitamatsu, Mizuki, Hayashi, Yuri, Takenaka, Fumiaki, Nishiki, Tei-ichi, Matsui, Hideki
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.07.2015
• Subjects: Advanced Basic Science; Animals; Arginine - chemistry; Biomedical materials; Boron; Boron - chemistry; Boron Neutron Capture Therapy; Boron neutron capture therapy (BNCT); Boronic Acids - chemistry; Brain Neoplasms - pathology; Brain Neoplasms - radiotherapy; Brain tumor; BSH poly-arginine; Cell Line, Tumor; Cell Survival; Copper - chemistry; CPP; Dentistry; Disease Models, Animal; DOTA; Drug Delivery Systems; Female; Glioma; Glioma - radiotherapy; Heterocyclic Compounds, 1-Ring - chemistry; Humans; Imaging; Immunohistochemistry; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Oligopeptides - chemistry; Peptides - chemistry; PET; Positron emission; Positron-Emission Tomography; Surgical implants; TAT; Tomography; Tomography, X-Ray Computed; Tumors; Uptakes; Brain tumor; CPP; BSH poly-arginine; Glioma; TAT; Boron neutron capture therapy (BNCT); DOTA; PET
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2015.03.061

Abstract 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 with64 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.