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

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.

Improved Boron Neutron Capture Therapy Using Integrin αvβ3-Targeted Long-Retention-Type Boron Carrier in a F98 Rat Glioma Model

“…Each cell was provided by or purchased from as follows: F98 glioma cells, Dr. Rolf Barth (Ohio State University, Columbus, OH, USA); C6 glioma cells, the Japan Collection of Research Bioresources (JCRB) Cell Bank, National Institute of Biomedical Innovation (Osaka, Japan); 9L rat gliosarcoma cells, the American Type Culture Collection (ATCC; Manassas, VA, USA). All the cells were cultured in the medium that was used in our laboratory [ 16 , 32 , 33 , 34 , 35 , 36 ]. This medium contained Dulbecco’s modified Eagle’s medium (DMEM) and was supplemented with 10% fetal bovine serum, penicillin, streptomycin, and amphotericin B.…”

“…All the materials for making this culture medium were purchased from Gibco Invitrogen (Grand Island, NY, USA). Of these cell lines, F98 glioma cells are particularly useful in evaluating therapeutic agents [ 16 , 32 , 33 , 34 , 35 , 36 ] because they simulate the behavior of human malignant gliomas in intracerebral implantation, including their high-infiltrative growth pattern and low immunogenicity [ 37 , 38 ]. The F98 glioma-bearing rat brain tumor model was used for in vivo evaluation.…”

“…In this study, 10-week-old male Fischer rats (Japan SLC, Shizuoka, Japan) were used. Their weight was approximately 200–250 g. They were anesthetized through an intraperitoneal injection of mixed anesthetics that are routinely used by our group [ 16 , 32 , 33 , 34 , 35 , 36 ]. Using a stereotactic frame (IMPACT-1000C connected to Legato 130, MUROMACHI KIKAI Co., Ltd., Tokyo, Japan), the rat’s head was fixed, and F98 glioma cells diluted in a 10 µL solution of DMEM with 1.4% agarose (Wako Pure Chemical Industries, Osaka, Japan) were implanted into the right brain.…”

“…The size of the burr hole was 1 mm, and it was made at 1 mm posterior to the bregma, 4 mm to the right lateral side. These surgical procedures are routinely used by our group [ 16 , 32 , 33 , 34 , 35 , 36 ].…”

“…The equation D B + D N + D H + D γ was used, and each factor corresponded to 10 B(n,α) 7 Li, 14 N(n,p) 14 C, and 1 H(n,n) 1 H capture reactions and γ-rays, respectively. What D B , D N , D H , and D γ mean and how to calculate them have already reported, and the physical doses to the brain and brain tumors were calculated for each group and calculated according to [ 32 , 36 ]. The estimated photon-equivalent dose was calculated by the following equation: D B × CBE + D N × relative biological effectiveness (RBE N ) + D H × relative biological effectiveness (RBE H ) + D γ .…”