P. N. Lebedev Physical Institute of the Russian Academy of Sciences, Leninsky Prospect 53, Moscow 119991, Russia.
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 3 Institutskaya St., Pushchino 142290, Russia.
Molecules. 2024 Aug 21;29(16):3936. doi: 10.3390/molecules29163936.
Boron-enhanced proton therapy has recently appeared as a promising approach to increase the efficiency of proton therapy on tumor cells, and this modality can further be improved by the use of boron nanoparticles (B NPs) as local sensitizers to achieve enhanced and targeted therapeutic outcomes. However, the mechanisms of tumor cell elimination under boron-enhanced proton therapy still require clarification. Here, we explore possible molecular mechanisms responsible for the enhancement of therapeutic outcomes under boron NP-enhanced proton therapy. Spherical B NPs with a mode size of 25 nm were prepared by methods of pulsed laser ablation in water, followed by their coating by polyethylene glycol to improve their colloidal stability in buffers. Then, we assessed the efficiency of B NPs as sensitizers of cancer cell killing under irradiation with a 160.5 MeV proton beam. Our experiments showed that the combined effect of B NPs and proton irradiation induces an increased level of superoxide anion radical generation, which leads to the depolarization of mitochondria, a drop in their membrane mitochondrial potential, and the development of apoptosis. A comprehensive gene expression analysis (via RT-PCR) confirmed increased overexpression of 52 genes (out of 87 studied) involved in the cell redox status and oxidative stress, compared to 12 genes in the cells irradiated without B NPs. Other possible mechanisms responsible for the B NPs-induced radiosensitizing effect, including one related to the generation of alpha particles, are discussed. The obtained results give a better insight into the processes involved in the boron-induced enhancement of proton therapy and enable one to optimize parameters of proton therapy in order to maximize therapeutic outcomes.
硼增强质子治疗最近作为一种提高肿瘤细胞质子治疗效率的有前途的方法出现，这种方法可以通过使用硼纳米粒子（B NPs）作为局部敏化剂进一步得到改善，以实现增强和靶向的治疗效果。然而，硼增强质子治疗下肿瘤细胞消除的机制仍需要阐明。在这里，我们探讨了硼纳米粒子增强质子治疗增强治疗效果的可能分子机制。通过水的脉冲激光烧蚀方法制备了模式尺寸为 25nm 的球形 B NPs，然后用聚乙二醇对其进行涂层处理，以提高其在缓冲液中的胶体稳定性。然后，我们评估了 B NPs 作为在 160.5MeV 质子束照射下杀伤癌细胞的敏化剂的效率。我们的实验表明，B NPs 和质子辐照的联合作用诱导超氧阴离子自由基生成水平增加，导致线粒体去极化，线粒体膜电位下降，细胞凋亡。综合基因表达分析（通过 RT-PCR）证实，与未用 B NPs 照射的细胞相比，有 52 个基因（87 个研究基因中的 52 个）涉及细胞氧化还原状态和氧化应激的过度表达，而只有 12 个基因过度表达。还讨论了其他可能与 B NPs 诱导的放射增敏作用有关的机制，包括与产生α粒子有关的机制。所得到的结果使我们更好地了解了硼增强质子治疗中涉及的过程，并能够优化质子治疗的参数，以最大限度地提高治疗效果。
