TY - JOUR

T1 - Accelerator-based boron neutron capture therapy for malignant glioma

T2 - a pilot neutron irradiation study using boron phenylalanine, sodium borocaptate and liposomal borocaptate with a heterotopic U87 glioblastoma model in SCID mice

AU - Zavjalov, Evgenii

AU - Zaboronok, Alexander

AU - Kanygin, Vladimir

AU - Kasatova, Anna

AU - Kichigin, Aleksandr

AU - Mukhamadiyarov, Rinat

AU - Razumov, Ivan

AU - Sycheva, Tatiana

AU - Mathis, Bryan J.

AU - Maezono, Sakura Eri B.

AU - Matsumura, Akira

AU - Taskaev, Sergey

PY - 2020/7/2

Y1 - 2020/7/2

N2 - Purpose: To evaluate the efficacy of boron neutron capture therapy (BNCT) for a heterotopic U87 glioblastoma model in SCID mice using boron phenylalanine (BPA), sodium borocaptate (BSH) and liposomal BSH as boron compounds at a unique, accelerator-based neutron source. Materials and methods: Glioblastoma models were obtained by subcutaneous implantation of U87 cells in the right thighs of SCID mice before administration of 350 mg/kg of BPA (BPA-group), 100 mg/kg of BSH (BSH-group) or 100 mg/kg of BSH in PEGylated liposomes (liposomal BSH-group) into the retroorbital sinus. Liposomes were prepared by reverse-phase evaporation. Neutron irradiation was carried out at a proton accelerator with a lithium target developed for BNCT at the Budker Institute of Nuclear Physics, Novosibirsk, Russian Federation. A proton beam current integral of 3 mA/h and energy of 2.05 MeV were used for neutron generation. Results: Boron compound accumulation in tumor tissues at the beginning of irradiation was higher in the BPA group, followed by the Liposomal BSH and BSH groups. Tumor growth was significantly slower in all irradiated mice from the 7th day after BNCT compared to untreated controls (p <.05). Tumor growth in all treated groups showed no large variation, apart from the Irradiation only group and the BPA group on the 7th day after BNCT. The overall trend of tumor growth was clear and the differences between treatment groups became significant from the 50th day after BNCT. Tumor growth was significantly slower in the Liposomal BSH group compared to the Irradiation only group on the 50th (p =.012), 53rd (p =.005), and the 57th (p =.021) days after treatment. Tumor growth in the Liposomal BSH group was significantly different from that in the BPA group on the 53rd day after BNCT (p =.021) and in the BSH group on the 50th (p =.024), 53rd (p =.015), and 57th (p =.038) days after BNCT. Skin reactions in the form of erosions and ulcers in the tumor area developed in treated as well as untreated animals with further formation of fistulas and necrotic decay cavities in most irradiated mice. Conclusions: We observed a tendency of BNCT at the accelerator-based neutron source to reduce or suspend the growth of human glioblastoma in immunodeficient animals. Liposomal BSH showed better long-term results compared to BPA and non-liposomal BSH. Further modifications in liposomal boron delivery are being studied to improve treatment outcomes.

AB - Purpose: To evaluate the efficacy of boron neutron capture therapy (BNCT) for a heterotopic U87 glioblastoma model in SCID mice using boron phenylalanine (BPA), sodium borocaptate (BSH) and liposomal BSH as boron compounds at a unique, accelerator-based neutron source. Materials and methods: Glioblastoma models were obtained by subcutaneous implantation of U87 cells in the right thighs of SCID mice before administration of 350 mg/kg of BPA (BPA-group), 100 mg/kg of BSH (BSH-group) or 100 mg/kg of BSH in PEGylated liposomes (liposomal BSH-group) into the retroorbital sinus. Liposomes were prepared by reverse-phase evaporation. Neutron irradiation was carried out at a proton accelerator with a lithium target developed for BNCT at the Budker Institute of Nuclear Physics, Novosibirsk, Russian Federation. A proton beam current integral of 3 mA/h and energy of 2.05 MeV were used for neutron generation. Results: Boron compound accumulation in tumor tissues at the beginning of irradiation was higher in the BPA group, followed by the Liposomal BSH and BSH groups. Tumor growth was significantly slower in all irradiated mice from the 7th day after BNCT compared to untreated controls (p <.05). Tumor growth in all treated groups showed no large variation, apart from the Irradiation only group and the BPA group on the 7th day after BNCT. The overall trend of tumor growth was clear and the differences between treatment groups became significant from the 50th day after BNCT. Tumor growth was significantly slower in the Liposomal BSH group compared to the Irradiation only group on the 50th (p =.012), 53rd (p =.005), and the 57th (p =.021) days after treatment. Tumor growth in the Liposomal BSH group was significantly different from that in the BPA group on the 53rd day after BNCT (p =.021) and in the BSH group on the 50th (p =.024), 53rd (p =.015), and 57th (p =.038) days after BNCT. Skin reactions in the form of erosions and ulcers in the tumor area developed in treated as well as untreated animals with further formation of fistulas and necrotic decay cavities in most irradiated mice. Conclusions: We observed a tendency of BNCT at the accelerator-based neutron source to reduce or suspend the growth of human glioblastoma in immunodeficient animals. Liposomal BSH showed better long-term results compared to BPA and non-liposomal BSH. Further modifications in liposomal boron delivery are being studied to improve treatment outcomes.

KW - accelerator-based neutron source

KW - Boron neutron capture therapy

KW - BPA

KW - BSH

KW - glioma

KW - liposomes

KW - BORONOPHENYLALANINE

KW - BEAM

KW - BNCT

KW - SELECTIVE DELIVERY

KW - TUMORS

UR - http://www.scopus.com/inward/record.url?scp=85084844397&partnerID=8YFLogxK

U2 - 10.1080/09553002.2020.1761039

DO - 10.1080/09553002.2020.1761039

M3 - Article

C2 - 32339057

AN - SCOPUS:85084844397

VL - 96

SP - 868

EP - 878

JO - International Journal of Radiation Biology

JF - International Journal of Radiation Biology

SN - 0955-3002

IS - 7

ER -