Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Turin, Italy.
Department of Chemistry, University of Torino, Via P. Giuria 7, 10125, Turin, Italy.
Sci Rep. 2020 Nov 6;10(1):19274. doi: 10.1038/s41598-020-76370-1.
This study aims at merging the therapeutic effects associated to the inhibition of Carbonic Anhydrase IX (CAIX), an essential enzyme overexpressed by cancer cells including mesothelioma and breast cancer, with those ones brought by the application of Boron Neutron Capture Therapy (BNCT). This task was pursued by designing a sulfonamido-functionalised-carborane (CA-SF) that acts simultaneously as CAIX inhibitor and boron delivery agent. The CAIX expression, measured by Western blot analysis, resulted high in both mesothelioma and breast tumours. This finding was exploited for the delivery of a therapeutic dose of boron (> 20 μg/g) to the cancer cells. The synergic cytotoxic effects operated by the enzymatic inhibition and neutron irradiation was evaluated in vitro on ZL34, AB22 and MCF7 cancer cells. Next, an in vivo model was prepared by subcutaneous injection of AB22 cells in Balb/c mice and CA-SF was administered as inclusion complex with a β-cyclodextrin oligomer. After irradiation with thermal neutrons tumour growth was evaluated for 25 days by MRI. The obtained results appear very promising as the tumour growth was definitively markedly lower in comparison to controls and the CAIX inhibitor alone. This approach appears promising and it call consideration for the design of new therapeutic routes to cure patients affected by this disease.
本研究旨在将碳酸酐酶 IX（CAIX）抑制相关的治疗效果与硼中子俘获治疗（BNCT）的治疗效果相结合。CAIX 是一种在包括间皮瘤和乳腺癌在内的癌细胞中过度表达的必需酶。通过设计一种同时作为 CAIX 抑制剂和硼供体的磺酰胺基功能化碳硼烷（CA-SF）来实现这一目标。通过 Western blot 分析测量 CAIX 的表达，结果表明间皮瘤和乳腺癌肿瘤中的 CAIX 表达均很高。这一发现被用于向癌细胞输送治疗剂量的硼（>20μg/g）。在 ZL34、AB22 和 MCF7 癌细胞上评估了酶抑制和中子辐照协同的细胞毒性作用。然后，通过在 Balb/c 小鼠中皮下注射 AB22 细胞制备体内模型，并将 CA-SF 作为与β-环糊精低聚物的包合物给药。用热中子辐照后，通过 MRI 在 25 天内评估肿瘤生长情况。与对照组和单独使用 CAIX 抑制剂相比，肿瘤生长明显降低，这一结果非常有前景。这种方法很有前途，值得考虑为治疗这种疾病的患者设计新的治疗途径。
