Multi-Targeted Neutron Capture Therapy Combined with an 18 kDa Translocator Protein-Targeted Boron Compound Is an Effective Strategy in a Rat Brain Tumor Model

SIMPLE SUMMARY: In recent years, boron neutron capture therapy (BNCT) has attracted attention as a treatment for high-grade gliomas, and clinical trials using an accelerator-based neutron source have shown its effectiveness. However, high-grade gliomas are still diseases that cannot be cured, and drug discovery of novel boron compounds has been actively pursued. We investigated the feasibility of boron neutron capture therapy targeting the 18 kDa translocator protein (TSPO), which is expressed in glioblastoma and surrounding environmental cells. In combination with an existing drug, boronophenylalanine (BPA), we obtained an add-on effect to neutron capture therapy in an experimental F98 rat glioma bearing brain tumor model. The potential to provide multi-targeted neutron capture therapy by combining boron compounds with different biological targeting properties was demonstrated. ABSTRACT: Background: Boron neutron capture therapy (BNCT) has been adapted to high-grade gliomas (HG); however, some gliomas are refractory to BNCT using boronophenylalanine (BPA). In this study, the feasibility of BNCT targeting the 18 kDa translocator protein (TSPO) expressed in glioblastoma and surrounding environmental cells was investigated. Methods: Three rat glioma cell lines, an F98 rat glioma bearing brain tumor model, DPA-BSTPG which is a boron-10 compound targeting TSPO, BPA, and sodium borocaptate (BSH) were used. TSPO expression was evaluated in the F98 rat glioma model. Boron uptake was assessed in three rat glioma cell lines and in the F98 rat glioma model. In vitro and in vivo neutron irradiation experiments were performed. Results: DPA-BSTPG was efficiently taken up in vitro. The brain tumor has 16-fold higher TSPO expressions than its brain tissue. The compound biological effectiveness value of DPA-BSTPG was 8.43 to F98 rat glioma cells. The boron concentration in the tumor using DPA-BSTPG convection-enhanced delivery (CED) administration was approximately twice as high as using BPA intravenous administration. BNCT using DPA-BSTPG has significant efficacy over the untreated group. BNCT using a combination of BPA and DPA-BSTPG gained significantly longer survival times than using BPA alone. Conclusion: DPA-BSTPG in combination with BPA may provide the multi-targeted neutron capture therapy against HG.