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

Abstract

Integrin αvβ3 is more highly expressed in high-grade glioma cells than in normal tissues. In this study, a novel boron-10 carrier containing maleimide-functionalized closo-dodecaborate (MID), serum albumin as a drug delivery system, and cyclic arginine-glycine-aspartate (cRGD) that can target integrin αvβ3 was developed. The efficacy of boron neutron capture therapy (BNCT) targeting integrin αvβ3 in glioma cells in the brain of rats using a cRGD-functionalized MID-albumin conjugate (cRGD-MID-AC) was evaluated. F98 glioma cells exposed to boronophenylalanine (BPA), cRGD-MID-AC, and cRGD + MID were used for cellular uptake and neutron-irradiation experiments. An F98 glioma-bearing rat brain tumor model was used for biodistribution and neutron-irradiation experiments after BPA or cRGD-MID-AC administration. BNCT using cRGD-MID-AC had a sufficient cell-killing effect in vitro, similar to that with BNCT using BPA. In biodistribution experiments, cRGD-MID-AC accumulated in the brain tumor, with the highest boron concentration observed 8 h after administration. Significant differences were observed between the untreated group and BNCT using cRGD-MID-AC groups in the in vivo neutron-irradiation experiments through the log-rank test. Long-term survivors were observed only in BNCT using cRGD-MID-AC groups 8 h after intravenous administration. These findings suggest that BNCT with cRGD-MID-AC is highly selective against gliomas through a mechanism that is different from that of BNCT with BPA.

Translational research of boron neutron capture therapy for spinal cord gliomas using rat model

“…BPA is taken up by tumor cells via L-type amino acid transporter 1 (LAT-1) 38 , which is highly expressed in tumor cells. In F98 glioma rat brain tumor models, a tumor-to-normal brain (T/N) ratio of ~ 3–4 has been reported 39 – 42 . Similarly, the present study focused on spinal cord tumor models, and the T/N (spinal cord tumor-to-normal spinal cord) ratio was also ~ 3–5, with nearly equivalent boron concentrations detected in the normal brain and normal spinal cord (Table 2 ).…”

“…In vitro experiments were performed using two tumor cell lines: F98 rat glioma cells and 9L rat gliosarcoma cells 46 . F98 rat glioma cells were kindly provided by Dr. Rolf Barth (Ohio State University, Columbus, OH, USA), and 9L rat gliosarcoma cells were purchased from the American Type Culture Collection (Manassas, VA, USA) 41 , 42 . All cell lines were cultured in Dulbecco’s Modified Eagle’s Medium (DMEM), supplemented with 10% fetal bovine serum and penicillin, streptomycin, and amphotericin B at 37℃ under 5% CO 2 .…”

“…All cell lines were cultured in Dulbecco’s Modified Eagle’s Medium (DMEM), supplemented with 10% fetal bovine serum and penicillin, streptomycin, and amphotericin B at 37℃ under 5% CO 2 . All materials used in the culture medium were purchased from Gibco (Grand Island, NY) 39 – 42 . Of the two cell lines, F98 rat glioma cells were used in our laboratory for basic research on BNCT for intracranial malignant glioma 39 – 42 .…”

“…All materials used in the culture medium were purchased from Gibco (Grand Island, NY) 39 – 42 . Of the two cell lines, F98 rat glioma cells were used in our laboratory for basic research on BNCT for intracranial malignant glioma 39 – 42 . F98 rat glioma cells can simulate the behavior of human malignant gliomas during intracerebral implantation, including their highly infiltrative growth pattern and low immunogenicity 46 , 47 .…”

“…Cellular boron uptake by F98 glioma and 9L gliosarcoma cells exposed to BPA was examined in vitro. Initially, cells at a density of 5.0 × 10 5 were seeded in 100-mm dishes (Becton, Dickinson, and Company, Franklin Lakes, NJ, USA) and incubated at 37℃ under a 5% CO 2 atmosphere using the above-described culture medium 39 , 41 , 42 . After three days of incubation, the culture medium was replaced with a culture medium containing 5, 10, or 20 µg B/mL BPA and incubated for 2.5 h under the same conditions.…”