Evaluation of the Potential of 2-Amino-3-(1,7-dicarba-closo-dodecaboranyl-1-thio)propanoic Acid as a Boron Neutron Capture Therapy Agent

Abstract

A novel boron-rich α-amino acid (3) that serves as a boron delivery agent for boron neutron capture therapy (BNCT) has been designed and synthesized by substituting the side chain of cysteine with m-carborane. The uptake of this compound into neuronal U87 cells was determined by inductively coupled plasma-optical emission spectrometry (ICP-OES) and showed intracellular concentrations of elemental boron at the picogram/cell level. To assess the cell-killing effect of 3, U87 cells were incubated with varying concentrations of 3 and 1 mM of the known BNCT agent 4-borono-l-phenylalanine (BPA) for comparison. Cells were subsequently exposed to radiation with thermal neutrons at fluences varying from 1 × 108 to 2 × 109 neutrons/cm2. Prior to neutron beam exposure, no cytotoxic effect was observed for BPA-treated cells, while a modest cytotoxic effect was observed for cells incubated with concentrations of 3 varying from 1 μM to 1 mM (resulting in cell viability reductions from 2.1% to 12.5%, respectively, relative to the control). An enhanced cell-killing effect (with a cell viability reduction of up to 47.8% relative to the control) was observed when 3-treated cells were irradiated with thermal neutrons. This was attributed to the impact of α particle formation from 3 in response to neutron beam exposure. Lower concentrations of 3 exhibited a superior cytotoxic effect relative to BPA and at reduced levels of neutron fluences when compared to that used in conventional treatment. This work suggests the potential for a novel “chemo-radiotherapy” approach to the treatment of cancer by BNCT, whereby a 1000-fold lower neutron radiation fluence compared to typical BNCT can be used.