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

Biomaterials. 2015 Jul:56:10-7. doi: 10.1016/j.biomaterials.2015.03.061. Epub 2015 Apr 15.

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 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.

Keywords: BSH poly-arginine; Boron neutron capture therapy (BNCT); Brain tumor; CPP; DOTA; Glioma; PET; TAT.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginine / chemistry
  • Boron / chemistry
  • Boron Neutron Capture Therapy*
  • Boronic Acids / chemistry*
  • Brain Neoplasms / pathology
  • Brain Neoplasms / radiotherapy*
  • Cell Line, Tumor
  • Cell Survival
  • Copper / chemistry
  • Disease Models, Animal
  • Drug Delivery Systems*
  • Female
  • Glioma / radiotherapy
  • Heterocyclic Compounds, 1-Ring / chemistry*
  • Humans
  • Immunohistochemistry
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Transplantation
  • Oligopeptides / chemistry*
  • Peptides / chemistry
  • Positron-Emission Tomography
  • Tomography, X-Ray Computed

Substances

  • Boronic Acids
  • Heterocyclic Compounds, 1-Ring
  • Oligopeptides
  • Peptides
  • 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
  • Copper
  • Arginine
  • Boron