纳秒脉冲高频透膜效应优先杀伤化疗抗性肿瘤细胞的仿真与实验研究

doi:10.19595/j.cnki.1000-6753.tces.181456

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Abstract In order to overcome the barrier of clinical tumor treatment—chemoresistance, and to make up for the blank of bioelectric effect on chemoresistance tumor cells (CRTCs) induced by nanosecond pulse electric fields (nsPEFs), simulations and experiments were combined in this paper. Firstly, based on the finite element platform, a five-layer dielectric model considering organelles and a numerical model considering the electroporation of inner and outer membranes were established. The high-frequency permeation effect, targeting characteristics and the influence from cell nucleus size were analyzed. Then, taking A549 and homologous A549/R as research objects, this paper further studied the fluorescence dissipation of inner/outer membrane under nsPEFs, and compared the differences of the morphology and killing effects between A549 and A549/R based on the fluorescent probe and flow techniques. It is shown that nsPEFs can efficiently target the inner membrane and induce the fluorescence dissipation of the cell nuclear membrane. This intracellular effect is positively correlated with the nucleus size (or nucleo-cytoplasmic ratio, NCR), causing higher killing effect on A549/R with higher NCR. Therefore, high voltage nsPEFs can target inner membrane to priority kill CRTCs. These results provide theoretical and experimental basis for selective killing of the CRTCs, and also lay a foundation for nsPEFs as a new physical selective method, which can be combined with other tumor treatment methods to achieve effective ablation of refractory tumor tissues.

Key words： Nanosecond pulse chemoresistance electroporation tumor treatment targeted ablation selectivity intracellular electromainpulation

Received: 10 September 2018 Published: 28 November 2019

PACS:	TM11
	TM836
	Q64

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	Liu Hongmei
	Dong Shoulong
	Ning Junyi
	Zheng Shuang
	Yao Chenguo

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Liu Hongmei,Dong Shoulong,Ning Junyi等. Simulation and Experimental Study on Preferential Killing of Chemoresistance Tumor Cells Induced by the High-Frequency Permeation Effect of Nanosecond Pulse Field[J]. Transactions of China Electrotechnical Society, 2019, 34(22): 4839-4848.

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https://dgjsxb.ces-transaction.com/EN/10.19595/j.cnki.1000-6753.tces.181456 OR https://dgjsxb.ces-transaction.com/EN/Y2019/V34/I22/4839

[1] Chen Wanqing, Zheng Rongshu, Baade P D, et al.Cancer statistics in China, 2015[J]. CA: A Cancer Journal for Clinicians, 2016, 66(2): 115-132.
[2] Malhotra V, Perry M C.Classical chemotherapy: mechanisms, toxicities and the therapeutc window[J]. Cancer Biology & Therapy, 2003, 2(S1): 1-3.
[3] Lind M J.Principles of chemotherapy[J]. Inter- national Journal of Gynecology & Obstetrics, 2016, 20(3): 123-128.
[4] Lind M J.Principles of cytotoxic chemotherapy[J]. Medicine, 2004, 32(3): 20-25.
[5] Zeng-Rong N, Paterson J, Alpert L, et al.Elevated DNA repair capacity is associated with intrinsic resistance of lung cancer to chemotherapy[J]. Cancer Research, 1995, 55: 4760-4764.
[6] Martin L P, Hamilton T C, Schilder R J.Platinum resistance: the role of DNA repair pathways[J]. Clinical Cancer Research an Official Journal of the American Association for Cancer Research, 2008, 14(5): 1291-1295.
[7] Townsend D M, Tew K D.The role of glutathione- S-transferase in anti-cancer drug resistance[J]. Oncogene, 2003, 22(7): 7369-7375.
[8] Oza A M.Clinical development of P-glycoprotein modulators in oncology[J]. Novartis Foundation Symposium, 2002, 243(1): 103-115.
[9] Solyanik G.Multifactorial nature of tumor drug resistance[J]. Experimental Oncology, 2010, 32(3): 181-185.
[10] Zhang Ruijie, Yao Wei, Qian Pin, et al.Increased sensitivity of human lung adenocarcinoma cells to cisplatin associated with downregulated contactin- 1[J]. Biomedicine & Pharmacotherapy, 2015, 71(1): 172-184.
[11] Yu Tinghe, Luo Li, Wang Li.Ultrasound as a cancer chemotherapy sensitizer: the gap between laboratory and bedside[J]. Expert Opinion on Drug Delivery, 2016, 13(1): 37-47.
[12] Yao Chengguo, Hu Xiaoqian, Mi Yao, et al.Window effect of pulsed electric field on biological cells[J]. IEEE Transactions on Dielectrics & Electrical Insulation, 2009, 16(5): 1259-1266.
[13] Schoenbach K H, Beebe S J, Buescher E S.Intracellular effect of ultrashort electrical pulses[J]. Bioelectromagnetics, 2010, 22(6): 440-448.
[14] Beebe S J, Sain N M, Ren W.Induction of cell death mechanisms and apoptosis by nanosecond pulsed electric fields (nsPEFs)[J]. Cells, 2013, 2(1): 136-162.
[15] Schoenbach K H, Joshi R P, Kolb J F, et al.Ultrashort electrical pulses open a new gateway into biological cells[J]. Proceedings of the IEEE, 2004, 92(7): 1122-1137.
[16] Miklavčič D, Serša G, Brecelj E, et al.Electro- chemotherapy: technological advancements for efficient electroporation-based treatment of internal tumors[J]. Medical & Biological Engineering & Computing, 2012, 50(12): 1213-1225.
[17] Nuccitelli R, Mcdaniel A, Anand S, et al.Nano-pulse stimulation is a physical modality that can trigger immunogenic tumor cell death[J]. Journal for Immunotherapy of Cancer, 2017, 5(1): 1-13.
[18] Nuccitelli R, Berridge J C, Mallon Z, et al.Nanoelectroablation of murine tumors triggers a CD8-dependent inhibition of secondary tumor growth[J]. Plos One, 2015, 10(7): e0134364.
[19] Tang Jingchao, Yin Hairong, Ma Jialu, et al.Terahertz electric field-induced membrane electro- poration by molecular dynamics simulations[J]. The Journal of Membrane Biology, 2018, 251(5-6): 681-693.
[20] 米彦, 彭文成, 芮少琴, 等. 高频纳秒脉冲串作用下皮肤肿瘤热效应的多参数有限元仿真与实验[J]. 电工技术学报, 2017, 32(22): 264-274.
Mi Yan, Peng Wencheng, Rui Shaoqin, et al.Thermal effects in skin tumor exposed to high-frequency nanosecond pulse bursts: multi-parametric finite element simulation and experiment[J]. Transactions of China Electrotechnical Society, 2017, 32(22): 264-274.
[21] 姚陈果, 吕彦鹏, 赵亚军, 等. 基于能量概率与微孔力模型的脉冲电场对细胞电穿孔动态过程的仿真分析[J]. 电工技术学报, 2016, 31(23): 141-149.
Yao Chenguo, Lü Yanpeng, Zhao Yajun, et al.Simulation analysis on dynamic process of electro- poration by the model based on energy probability and pore force in cell exposed to pulsed electric field[J]. Transactions of China Electrotechnical Society, 2016, 31(23): 141-149.
[22] 米彦, 徐进, 刘宏亮, 等. 基于网格传输网络模型的高频纳秒脉冲串作用下单细胞穿孔特性仿真[J]. 电工技术学报, 2018, 33(18): 41-54.
Mi Yan, Xu Jin, Liu Hongliang, et al.Simulation on perforation features in a single-cell system exposed to high-frequency nanosecond pulse bursts based on mesh transport network model[J]. Transactions of China Electrotechnical Society, 2018, 33(18): 41-54.
[23] 米彦, 孙才新, 姚陈果, 等. 基于等效电路模型的细胞内外膜跨膜电位频率响应[J]. 电工技术学报, 2007, 22(6): 6-11.
Mi Yan, Sun Caixin, Yao Chenguo, et al.Frequency response of transmembrane potential on cell inner and outer membrane based on equivalent circuit model[J]. Transactions of China Electrotechnical Society, 2007, 22(6): 6-11.
[24] 米彦, 姚陈果, 李成祥, 等. 基于场-路复合模型的细胞内外膜跨膜电位时频特性[J]. 电工技术学报, 2011, 26(2): 14-20, 33.
Mi Yan, Yao Chenguo, Li Chengxiang, et al.Timefrequency characteristics of transmembrane potentials on cellular inner and outer membranes based on dielectric-circuit compound model[J]. Transactions of China Electrotechnical Society, 2011, 26(2): 14-20, 33
[25] Yao Chenguo, Mi Yan, Li Chengxiang, et al.Study of transmembrane potentials on cellular inner and outer membrane frequency response model and its filter characteristic simulation[J]. IEEE Transactions on Biomedical Engineering, 2008, 55(7): 1792-1799.
[26] Ivey J W, Latouche E L, Sano M B, et al.Targeted cellular ablation based on the morphology of malignant cells[J]. Scientific Reports, 2015, 5: 17157.
[27] Nesin O M, Pakhomova O N, Xiao S, et al.Manipulation of cell volume and membrane pore comparison following single cell permeabilization with 60- and 600-ns electric pulses[J]. B BBA- Biomembranes, 2011, 1808(3): 792-801.
[28] Ivorra A, Rubinsky B.In vivo electrical impedance measurements during and after electroporation of rat liver[J]. Bioelectrochemistry, 2007, 70(2): 287-295.
[29] Pakhomov A G, Xiao S, Pakhomova O N, et al.Disassembly of actin structures by nanosecond pulsed electric field is a downstream effect of cell swelling[J]. Bioelectrochemistry, 2014, 100: 88-95.
[30] Zhuang Jie, Kolb J F.Time domain dielectric spectroscopy of nanosecond pulsed electric field induced changes in dielectric properties of pig whole blood[J]. Bioelectrochemistry, 2015, 103: 28-33.
[31] Yao Chenguo, Liu Hongmei, Zhao Yajun, et al.Analysis of dynamic processes in single-cell electro- poration and their effects on parameter selection based on the finite-element model[J]. IEEE Transactions on Plasma Science, 2017, 45(5): 1-12.
[32] Debruin K A, Krassowska W.Modeling electro- poration in a single cell. I. effects of field strength and rest potential[J]. Biophysical Journal, 1999, 77(3): 1213-1224.
[33] Neu J C, Krassowska W.Asymptotic model of electroporation[J]. Physical Review E, 1999, 59(3): 3471.
[34] Wegner L H, Frey W, Schönwälder S.A critical evaluation of whole cell patch clamp studies on electroporation using the voltage sensitive dye ANNINE-6[J]. Bioelectrochemistry, 2013, 92(8): 42-46.
[35] Craviso G L, Choe S, Chatterjee I, et al.Modulation of intracellular Ca²+ levels in chromaffin cells by nanoelectropulses[J]. Bioelectrochemistry, 2012, 87(10): 244-252.
[36] Rassokhin M A, Pakhomov A G.Electric field exposure triggers and guides formation of pseudopod- like blebs in U937 monocytes[J]. Journal of Membrane Biology, 2012, 245(9): 521-529.
[37] Tolstykh G P, Beier H T, Roth C C, et al.Activation of intracellular phosphoinositide signaling after a single 600 nanosecond electric pulse[J]. Bioelectro- chemistry, 2013, 94(12): 23-29.
[38] Ren Wei, Sain N M, Beebe S J.Nanosecond pulsed electric fields (nsPEFs) activate intrinsic caspase- dependent and caspase-independent cell death in Jurkat cells[J]. Biochemical & Biophysical Research Communications, 2012, 421(4): 808-812.