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冷大气压等离子体(cold atmospheric plasma, CAP)由于其具有“选择性”杀伤癌细胞的效果, 被认为是一种极具潜力的癌症治疗手段. 然而, CAP对癌细胞的“选择性”杀伤作用相关的物理模型及CAP与癌细胞相互作用的微观机理仍然匮乏. 本文采用分子动力学方法模拟了CAP激发电场引起的细胞膜电穿孔(electroporation, EP)效应, 并采用伞形采样法计算了活性氧物质(reactive oxygen species, ROS)通过EP形成的不同阶段的孔结构进入细胞内部的自由能剖面. 结果表明, 相较于正常细胞膜, 胆固醇含量较低的癌细胞膜发生EP的电场强度阈值更低, 且EP发生时间更快; 对于ROS的转运过程而言, 由于癌细胞膜胆固醇含量更低, 在EP的各个阶段下ROS的自由能势垒更低, 因此在EP的各个阶段下, ROS内流的时间均早于正常细胞. 本文从分子模拟的角度探索了CAP激发电场作用下EP的形成过程, 以及EP的不同阶段中ROS转运的潜在机会, 有利于更清楚地阐述CAP“选择性”抗癌作用的微观机理, 并为CAP癌症治疗技术、设备和手段的研发提供了重要参考, 促进了CAP在临床应用方面的发展.Cold atmospheric plasma (CAP) is considered to be a highly promising cancer treatment method, due to its “selective” anti-cancer effect. However, the physical theoretical explanation about this effect and the microscopic interactive mechanisms between CAP and tumors are still lacking. In this work, the CAP-induced electric field-caused electroporation (EP) processes of the cell membrane are modeled based on molecular dynamics. Additionally, the umbrella sampling method is utilized to compute the free energy profile of the intracellular permeation processes of the reactive oxygen species (ROS) through EP-formed pore-like structures at different EP stages. Comparative results are shown as follows. 1) Cancer cell membranes with lower cholesterol components show lower EP-generation threshold and faster EP-formation, and 2) lower free-energy barrier and earlier occurrence of free-energy barrier reduction are shown in all EP stages in cancer cell membrane. The above results explain the difference between cancer cells and normal cells when affected by CAP. Our work delves into the formation of CAP-induced EP and the transport of ROS through EP-formed pore-like structures, which contributes to a better understanding of the microscopic mechanisms of the “selective” anti-cancer effect of CAP, and provides important references for developing CAP-based cancer treatment methods, and devices, thereby facilitating the translation of CAP into clinical applications.
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Keywords:
- cold atmospheric plasma /
- electric field /
- cell membrane electroporation /
- molecular dynamics
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表 1 不同胆固醇含量的细胞膜模型参数
Table 1. Cell membrane model parameters with different cholesterol content.
序号 POPC数量 胆固醇数量 胆固醇含量/% 水分子数 X/nm Y/nm Z/nm 模型1 128 0 0 4873 6.03 6.03 9.07 模型2 112 16 12.5 4705 5.94 5.94 8.25 模型3 102 26 20.3 4513 5.78 5.78 8.39 -
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