替莫唑胺的硼化衍生物在胶质母细胞瘤硼中子俘获治疗中显示出增强的疗效。
A Boronated Derivative of Temozolomide Showing Enhanced Efficacy in Boron Neutron Capture Therapy of Glioblastoma.
机构信息
Department of Biomedical Engineering, College of Engineering, Peking University, Beijing 100871, China.
Shenzhen Bay Laboratory, Institute of Biomedical Engineering, Shenzhen 518132, China.
出版信息
Cells. 2022 Mar 31;11(7):1173. doi: 10.3390/cells11071173.
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 B-boronated derivative of temozolomide, TMZB. BNCT was carried out with a total neutron radiation fluence of 2.4 ± 0.3 × 10 n/cm. The effects of TMZB in BNCT were measured with a clonogenic cell survival assay in vitro and PET/CT imaging in vivo. Then, 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.
由于胶质母细胞瘤对传统放化疗具有极强的耐药性，因此非常需要改进的治疗方式。硼中子俘获治疗（BNCT）可能在未来发挥作用。我们设计并合成了替莫唑胺的 B-硼代衍生物 TMZB。BNCT 采用总中子辐射通量为 2.4 ± 0.3 × 10 n/cm 进行。TMZB 在 BNCT 中的作用通过体外集落形成细胞存活测定和体内 PET/CT 成像进行测量。然后，平行测试了 B-硼代苯丙氨酸（BPA）与 TMZB 进行比较。TMZB 对 HS683 集落形成细胞的细胞毒性的 IC50 为 0.208 mM，与替莫唑胺的 IC50（0.213 mM）相当。在 BNCT 治疗中，0.243 mM TMZB 导致 91.2% ± 6.4%的集落形成细胞死亡，而 0.239 mM BPA 消除了 63.7% ± 6.3%的集落形成细胞。TMZB 在小鼠胶质母细胞瘤模型中的肿瘤与正常脑比值为 2.9 ± 1.1，肿瘤与血液比值为 3.8 ± 0.2。在该模型中，TMZB 联合 BNCT 引起 58.2%的肿瘤缩小，而 BPA 为 35.2%。因此，通过将替莫唑胺的化疗作用与 BNCT 的重带电粒子放疗相结合，TMZB 基 BNCT 显示出在胶质母细胞瘤治疗中具有有前途的治疗应用潜力。
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