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Among the great variety of anti-cancer therapeutic strategies, boron neutron capture therapy (BNCT) represents a unique approach that doubles the targeting accuracy due to the precise positioning of a neutron beam and the addressed delivery of boron compounds. We have recently demonstrated the principal possibility of using a cell-specific 2'-F-RNA aptamer for the targeted delivery of boron clusters for BNCT. In the present study, we evaluated the amount of boron-loaded aptamer inside the cell via two independent methods: quantitative real-time polymerase chain reaction and inductive coupled plasma-atomic emission spectrometry. Both assays showed that the internalized boron level inside the cell exceeds 1 × 10 9 atoms/cell. We have synthesized closo -dodecaborate conjugates of 2'-F-RNA aptamers GL44 and Waz, with boron clusters attached either at the 3'- or at the 5'-end. The influence of cluster localization was evaluated in BNCT experiments on U-87 MG human glioblastoma cells and normal fibroblasts and subsequent analyses of cell viability via real-time cell monitoring and clonogenic assay. Both conjugates of GL44 aptamer provided a specific decrease in cell viability, while only the 3'-conjugate of the Waz aptamer showed the same effect. Thus, an individual adjustment of boron cluster localization is required for each aptamer. The efficacy of boron-loaded 2'-F-RNA conjugates was comparable to that of 10 B-boronophenylalanine, so this type of boron delivery agent has good potential for BNCT due to such benefits as precise targeting, low toxicity and the possibility to use boron clusters made of natural, unenriched boron.

There is an incontestable need for improved treatment modality for glioblastoma due to its extraordinary resistance to traditional chemoradiation therapy. Boron neutron capture therapy (BNCT) may play a role in the future. We designed and synthesized a 10 B-boronated derivative of temozolomide, TMZB. BNCT was carried out with a total neutron radiation fluence of 2.4 ± 0.3 × 10 11 n/cm 2 . The effects of TMZB in BNCT were measured with a clonogenic cell survival assay in vitro and PET/CT imaging in vivo. Then, 10 B-boronated phenylalanine (BPA) was tested in parallel with TMZB for comparison. The IC50 of TMZB for the cytotoxicity of clonogenic cells in HS683 was 0.208 mM, which is comparable to the IC50 of temozolomide at 0.213 mM. In BNCT treatment, 0.243 mM TMZB caused 91.2% ± 6.4% of clonogenic cell death, while 0.239 mM BPA eliminated 63.7% ± 6.3% of clonogenic cells. TMZB had a tumor-to-normal brain ratio of 2.9 ± 1.1 and a tumor-to-blood ratio of 3.8 ± 0.2 in a mouse glioblastoma model. BNCT with TMZB in this model caused 58.2% tumor shrinkage at 31 days after neutron irradiation, while the number for BPA was 35.2%. Therefore, by combining the effects of chemotherapy from temozolomide and radiotherapy with heavy charged particles from BNCT, TMZB-based BNCT exhibited promising potential for therapeutic applications in glioblastoma treatment.

Among the great variety of anti-cancer therapeutic strategies, boron neutron capture therapy (BNCT) represents a unique approach that doubles the targeting accuracy due to the precise positioning of a neutron beam and the addressed delivery of boron compounds. We have recently demonstrated the principal possibility of using a cell-specific 2′-F-RNA aptamer for the targeted delivery of boron clusters for BNCT. In the present study, we evaluated the amount of boron-loaded aptamer inside the cell via two independent methods: quantitative real-time polymerase chain reaction and inductive coupled plasma–atomic emission spectrometry. Both assays showed that the internalized boron level inside the cell exceeds 1 × 109 atoms/cell. We have synthesized closo-dodecaborate conjugates of 2′-F-RNA aptamers GL44 and Waz, with boron clusters attached either at the 3′- or at the 5′-end. The influence of cluster localization was evaluated in BNCT experiments on U-87 MG human glioblastoma cells and normal fibroblasts and subsequent analyses of cell viability via real-time cell monitoring and clonogenic assay. Both conjugates of GL44 aptamer provided a specific decrease in cell viability, while only the 3′-conjugate of the Waz aptamer showed the same effect. Thus, an individual adjustment of boron cluster localization is required for each aptamer. The efficacy of boron-loaded 2′-F-RNA conjugates was comparable to that of 10B-boronophenylalanine, so this type of boron delivery agent has good potential for BNCT due to such benefits as precise targeting, low toxicity and the possibility to use boron clusters made of natural, unenriched boron. [ABSTRACT FROM AUTHOR]