不可逆电穿孔治疗肿瘤的作用机理及临床应用关键技术的研究
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摘要
肿瘤治疗是当今世界公认的公共卫生难题之一。由于受适应症、禁忌症等因素限制以及治疗副作用的影响,现有肿瘤治疗方法的疗效均不甚理想。不可逆电穿孔治疗肿瘤技术,作为一种新的肿瘤治疗方法,具有现有物理治疗方法无法比拟的优势,表现出良好的临床应用前景。
然而,任何一种治疗方法,由学术思想发展成为真正可供临床应用的技术,必须明确治疗机理、完善治疗设备并解决临床应用中所涉及的若干关键问题。为此,本文在国家自然科学基金重点项目《陡脉冲不可逆性电击穿治疗肿瘤的作用机理及关键技术研究》(批准号:50637020)的支持下,深入研究不可逆电穿孔治疗肿瘤的作用机制,并着力解决该方法在临床推进中的几个关键问题。论文的主要工作有:
①研究脉冲电场作用下细胞膜的穿孔机理。建立了含二棕榈酰磷脂酰胆碱的脂质双分子层膜模型,对脉冲电场作用下分子的排列方式及孔洞开放过程进行了仿真分析,发现了穿孔过程中分子的排列规律,提出了脉冲电场诱导脂质分子偶极子重排和疏水基团翻转导致细胞膜出现孔洞的穿孔机理;建立了脉冲电场作用下细胞膜的电场应力模型,提出了基于细胞膜受力分析获取外加脉冲电场场强阈值参数的思路。
②研究脉冲电场对肿瘤细胞的作用机制。以人宫颈癌HeLa细胞为研究对象,系统研究了诱导细胞发生可逆电穿孔、不可逆电穿孔及凋亡的脉冲电场的场强参数,首次提出了微秒脉冲电场的“窗口效应”及其“重叠特性”;研究了微秒脉冲电场致肿瘤细胞死亡的过程,首次提出了低场强诱发细胞凋亡并导致不可逆穿孔、高场强诱导细胞不可逆电穿孔而坏死的脉冲电场作用机制;分别对脉冲电场处理后细胞的粘附、侵袭和迁移能力进行了研究,研究了微秒脉冲电场对肿瘤细胞转移能力的影响及其可能的机理。
③研究不可逆电穿孔治疗肿瘤技术临床应用的有效性和安全性。选择肝脏肿瘤为不可逆电穿孔治疗技术的适应症,以荷瘤裸鼠为研究对象,通过分析治疗后的抑瘤曲线和生存率曲线等研究了不可逆电穿孔技术对于肝部肿瘤治疗的有效性;以南疆黄羊在体肝脏组织为对象,研究了用B超引导治疗过程和评估治疗效果的可行性,论证了不可逆电穿孔治疗范围的可控性及安全性。
④研究不可逆电穿孔治疗肿瘤技术临床治疗参数的优化问题。以静电场分布理论为基础,结合生物热传导理论,提出了一种基于电场和温度场仿真计算,优化脉冲电压幅值、电极针间距离和入针深度等临床治疗参数的方法,并提出一种综合考虑杀伤范围、治疗温度等多种约束条件的治疗参数优化模型的思路,为不可逆电穿孔技术临床治疗参数的确定提供科学的定量依据。
⑤研制不可逆电穿孔肿瘤治疗仪样机。基于脉冲功率技术中电容充放电原理,结合高压大功率电力电子开关技术和测控技术,研制了一套不可逆电穿孔肿瘤治疗仪样机。实验表明,该样机稳定可靠,能精确控制输出微秒级方波脉冲的输出电压、脉冲宽度、重复频率和脉冲个数。
综上所述,论文从分子动力学角度研究了电场脉冲诱导细胞不可逆电穿孔效应的作用机理,在细胞实验的基础上提出了微秒脉冲电场致细胞不可逆电穿孔的作用机制,系统研究了不可电穿孔技术临床应用的有效性、安全性及超声引导可行性等关键技术问题,提出了临床治疗参数的优化方法,研制并完善了新型治疗仪样机,为不可逆电穿孔治疗肿瘤技术的临床推进提供了必要的理论依据和技术支撑。
Tumor is the recognized public health problem all over the world, which is related to human health and life. However, existing therapies don’t work so well considering of the limits of their indications and contraindications as well as side effects. As a new idea of curing tumor, Irreversible electroporation (IRE) has a great advantage compared with the existing physical therapy and shows good clinical application.
Therefore, we work hard at the mechanisms of IRE treatment and try to solve the basic problems of key technologies involved when the academic thoughts are to be realized in the clinical application. So, an in-depth research is focused on IRE tumor treatment with the support of the national natural science foundation in key project‘Mechanism and key technology researches on IRE tumor treatment of short pulses’(grant No.50637020). The major achievements are as follows:
①Researches on mechanism of electroporation in the pulsed electric fields. A model of lipid bilayer containing DPPC was set up. The process of electroporation and its pore size in lipid bilayer was analyzed from the atomic level as well as the mechanism of electroporation formation; the balance equation of the molecular interaction within the cell membrane was constructed to calculate the change process of molecular interaction with the increase of the applied electric intensity.
②Researches on mechanism of tumor cells in the pulsed electric fields The electric intensity parameters that induced RE, IRE and apoptosis were analyzed systematically to study the window effect mechanism of the microsecond pulse electric intensity parameters when human cervical cancer HeLa cells were taken as research objects; typical electric pulse parameters were chosen to discuss the tumor cell death process induced by microsecond pulse electric fields and corresponding mechanism; adhesion, invasion and migration abilities of the cells treated by the pulse electric fields have been studied respectively. Accordingly, the effects of the transfer ability of tumor cells treated with microsecond pulses and the possible mechanisms were discussed.
③Researches on efficacy and safety of IRE tumor treatment in clinical applications. Liver cancer is taken as the indication of the IRE treatment and tumor-burdened nude mouse as the research objects. It has been confirmed that IRE is an effective method to cure liver cancer by observing the inhibitory curve and survival curves after treatments; the liver tissues of Nanjiang Gazelle were taken as research objects for the application in vivo of the IRE treatment. The feasibility of guiding the treatments and assessing the treatment effects by type-B ultrasonic has been discussed, and it was clarified that the treatment area was controllable, which proved the safety of the method.
④Researches on the parameter optimizations of IRE tumor treatment in clinical applications. Based on the electrostatic field distribution theory in combination with the bio-heat transfer theory, we explored the optimal combination of parameters of IRE treatment by the corresponding electric field and temperature field simulations while avoiding thermal effects. That is, the tumor cells were killed when the surrounding normal tissues were little suffered, which offered the references for the choice of the parameters of IRE treatment in clinical applications.
⑤Development of IRE treatment prototype. Combined with the high-voltage high-power electronic switches and triggering technology, control technology, a set of IRE tumor treatment device prototype has been developed on the basis of charge-discharge of the capacitor in traditional pulsed power technology. According to the debugging it showed that the prototype is stable and reliable, which is also able to control the output voltage, width, frequency and pulse number of output microsecond square wave pulses accurately.
In summary, this paper discussed the mechanism of the irreversible electroporation effect from the point of view of molecular dynamics and put forward the mechanism of irreversible electroporation induced by microsecond pulse electric field on the basic of the cell experiments. Besides, we also solved the key technical problems of effectiveness, safety and feasibility of ultrasound guide, proposed optimization strategy of treatment plan, developed and improved the novel treatment system prototype, which provided the material basis, theoretical basis and technical support for the clinical application of IRE tumor treatment.
然而,任何一种治疗方法,由学术思想发展成为真正可供临床应用的技术,必须明确治疗机理、完善治疗设备并解决临床应用中所涉及的若干关键问题。为此,本文在国家自然科学基金重点项目《陡脉冲不可逆性电击穿治疗肿瘤的作用机理及关键技术研究》(批准号:50637020)的支持下,深入研究不可逆电穿孔治疗肿瘤的作用机制,并着力解决该方法在临床推进中的几个关键问题。论文的主要工作有:
①研究脉冲电场作用下细胞膜的穿孔机理。建立了含二棕榈酰磷脂酰胆碱的脂质双分子层膜模型,对脉冲电场作用下分子的排列方式及孔洞开放过程进行了仿真分析,发现了穿孔过程中分子的排列规律,提出了脉冲电场诱导脂质分子偶极子重排和疏水基团翻转导致细胞膜出现孔洞的穿孔机理;建立了脉冲电场作用下细胞膜的电场应力模型,提出了基于细胞膜受力分析获取外加脉冲电场场强阈值参数的思路。
②研究脉冲电场对肿瘤细胞的作用机制。以人宫颈癌HeLa细胞为研究对象,系统研究了诱导细胞发生可逆电穿孔、不可逆电穿孔及凋亡的脉冲电场的场强参数,首次提出了微秒脉冲电场的“窗口效应”及其“重叠特性”;研究了微秒脉冲电场致肿瘤细胞死亡的过程,首次提出了低场强诱发细胞凋亡并导致不可逆穿孔、高场强诱导细胞不可逆电穿孔而坏死的脉冲电场作用机制;分别对脉冲电场处理后细胞的粘附、侵袭和迁移能力进行了研究,研究了微秒脉冲电场对肿瘤细胞转移能力的影响及其可能的机理。
③研究不可逆电穿孔治疗肿瘤技术临床应用的有效性和安全性。选择肝脏肿瘤为不可逆电穿孔治疗技术的适应症,以荷瘤裸鼠为研究对象,通过分析治疗后的抑瘤曲线和生存率曲线等研究了不可逆电穿孔技术对于肝部肿瘤治疗的有效性;以南疆黄羊在体肝脏组织为对象,研究了用B超引导治疗过程和评估治疗效果的可行性,论证了不可逆电穿孔治疗范围的可控性及安全性。
④研究不可逆电穿孔治疗肿瘤技术临床治疗参数的优化问题。以静电场分布理论为基础,结合生物热传导理论,提出了一种基于电场和温度场仿真计算,优化脉冲电压幅值、电极针间距离和入针深度等临床治疗参数的方法,并提出一种综合考虑杀伤范围、治疗温度等多种约束条件的治疗参数优化模型的思路,为不可逆电穿孔技术临床治疗参数的确定提供科学的定量依据。
⑤研制不可逆电穿孔肿瘤治疗仪样机。基于脉冲功率技术中电容充放电原理,结合高压大功率电力电子开关技术和测控技术,研制了一套不可逆电穿孔肿瘤治疗仪样机。实验表明,该样机稳定可靠,能精确控制输出微秒级方波脉冲的输出电压、脉冲宽度、重复频率和脉冲个数。
综上所述,论文从分子动力学角度研究了电场脉冲诱导细胞不可逆电穿孔效应的作用机理,在细胞实验的基础上提出了微秒脉冲电场致细胞不可逆电穿孔的作用机制,系统研究了不可电穿孔技术临床应用的有效性、安全性及超声引导可行性等关键技术问题,提出了临床治疗参数的优化方法,研制并完善了新型治疗仪样机,为不可逆电穿孔治疗肿瘤技术的临床推进提供了必要的理论依据和技术支撑。
Tumor is the recognized public health problem all over the world, which is related to human health and life. However, existing therapies don’t work so well considering of the limits of their indications and contraindications as well as side effects. As a new idea of curing tumor, Irreversible electroporation (IRE) has a great advantage compared with the existing physical therapy and shows good clinical application.
Therefore, we work hard at the mechanisms of IRE treatment and try to solve the basic problems of key technologies involved when the academic thoughts are to be realized in the clinical application. So, an in-depth research is focused on IRE tumor treatment with the support of the national natural science foundation in key project‘Mechanism and key technology researches on IRE tumor treatment of short pulses’(grant No.50637020). The major achievements are as follows:
①Researches on mechanism of electroporation in the pulsed electric fields. A model of lipid bilayer containing DPPC was set up. The process of electroporation and its pore size in lipid bilayer was analyzed from the atomic level as well as the mechanism of electroporation formation; the balance equation of the molecular interaction within the cell membrane was constructed to calculate the change process of molecular interaction with the increase of the applied electric intensity.
②Researches on mechanism of tumor cells in the pulsed electric fields The electric intensity parameters that induced RE, IRE and apoptosis were analyzed systematically to study the window effect mechanism of the microsecond pulse electric intensity parameters when human cervical cancer HeLa cells were taken as research objects; typical electric pulse parameters were chosen to discuss the tumor cell death process induced by microsecond pulse electric fields and corresponding mechanism; adhesion, invasion and migration abilities of the cells treated by the pulse electric fields have been studied respectively. Accordingly, the effects of the transfer ability of tumor cells treated with microsecond pulses and the possible mechanisms were discussed.
③Researches on efficacy and safety of IRE tumor treatment in clinical applications. Liver cancer is taken as the indication of the IRE treatment and tumor-burdened nude mouse as the research objects. It has been confirmed that IRE is an effective method to cure liver cancer by observing the inhibitory curve and survival curves after treatments; the liver tissues of Nanjiang Gazelle were taken as research objects for the application in vivo of the IRE treatment. The feasibility of guiding the treatments and assessing the treatment effects by type-B ultrasonic has been discussed, and it was clarified that the treatment area was controllable, which proved the safety of the method.
④Researches on the parameter optimizations of IRE tumor treatment in clinical applications. Based on the electrostatic field distribution theory in combination with the bio-heat transfer theory, we explored the optimal combination of parameters of IRE treatment by the corresponding electric field and temperature field simulations while avoiding thermal effects. That is, the tumor cells were killed when the surrounding normal tissues were little suffered, which offered the references for the choice of the parameters of IRE treatment in clinical applications.
⑤Development of IRE treatment prototype. Combined with the high-voltage high-power electronic switches and triggering technology, control technology, a set of IRE tumor treatment device prototype has been developed on the basis of charge-discharge of the capacitor in traditional pulsed power technology. According to the debugging it showed that the prototype is stable and reliable, which is also able to control the output voltage, width, frequency and pulse number of output microsecond square wave pulses accurately.
In summary, this paper discussed the mechanism of the irreversible electroporation effect from the point of view of molecular dynamics and put forward the mechanism of irreversible electroporation induced by microsecond pulse electric field on the basic of the cell experiments. Besides, we also solved the key technical problems of effectiveness, safety and feasibility of ultrasound guide, proposed optimization strategy of treatment plan, developed and improved the novel treatment system prototype, which provided the material basis, theoretical basis and technical support for the clinical application of IRE tumor treatment.
引文
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