Radiolysis, Photolysis and Sonolysis of Cells

细胞的放射分解、光解和超声波分解

• 批准号: 7066864
• 负责人: PETER RIESZ
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7066864
• 关键词: chemosensitizing agent; combination cancer therapy; cytolysis; drug interactions; electron spin resonance spectroscopy; free radical oxygen; free radical scavengers; neoplasm /cancer thermotherapy; physical chemical interaction; porphyrins; surfactant; temperature; tissue /cell culture; ultrasound biological effect; ultrasound therapy

Summary of work:Sonodynamic therapy is a promising new modality for cancer treatment based on the synergistic effects of cell killing by a combination of sonosensitzer and ultrasound. Ultrasound can penetrate deeply into tissue and can be focused in a small region of tumor to activate non-toxic molecules (e.g. porphyrins ) thus minimizing undesirable side effects. The experimental evidence suggests that sonosensitization is due to the chemical activation of sonosensitizers inside or in close vicinity of hot collapsing cavitation bubbles to form sensitizer-derived radicals either by direct pyrolysis of the sensitizer at the water-gas interface or due to the reactions of hydrogen atoms and hydroxyl radicals formed by the pyrolysis of water. The free radicals derived from the sonosensitizer (mostly carbon-centered) react with oxygen to form peroxyl and alkoxyl radicals. Unlike OH radicals and H atoms which are formed by pyrolysis inside cavitation bubbles, the reactivity of alkoxyl and peroxyl radicals with organic compounds in biological media is much lower and hence they have a higher probability of reaching critical cellular sites.The synergistic effect of ultrasound (47 kHz) and analogues of gallium-porphyrin derivatives (ATX-70) on cytolysis of human leukemia cells (HL-525 and HL-60) suspended in a cell culture medium were studied. Organic surfactants preferentially accumulate and subsequently decompose at the gas/solution interface of cavitation bubble, producing secondary radicals that can diffuse to the bulk solution. The gallium porphyrin analogues used in the current study possessed two n-alkyl side chains (ATX-Cx, where x = number of carbon atoms, ranging from x = 2 to x = 12). By varying the n-alkyl chain length, thereby modifying the surfactant properties of the ATX-Cx derivatives, cell killing in relation to the accumulation of the ATX-Cx derivatives at the gas/solution interface of cavitation bubbles was determined. Following sonolysis in the presence of the ATX-Cx, a strong correlation for the yield of carbon centered radicals and cell killing was observed. These results support the hypothesis that a sonochemical mechanism is responsible for the synergistic effect of ultrasound and ATX-Cx on HL-525 and HL-60 cells. Studies of the ultrasound-induced apoptosis and lysis of U937 cells by a hypotonic medium support the hypothesis that non-lethal hypotonia can enhance ultrasound-induced cell-killing. Ultrasound-induced killing of U937 cells was enhanced by azobis(2-amidinopropane)dihydrochloride. These findings suggest the clinical potential of temperature-dependent free radical generators in cancer therapy by ultrasound. The mechanism of sonodynamic therapy is probably not governed by a universal mechanism, but may be influenced by multiple factors including the nature of the biological model, the sonosensitizer and the ultrasound prameters.1.Ogawa, R.; Kondo, T.; Mori, H.; Zhao, Q.L.; Fukuda, S.; Riesz, P.: Effects of dissolved gases on ultrasound mediated in vitro gene transfection. Ultrasonics Sonochemistry, 9, 197-203, 2002.2.Feril, L.B.; Kondo, T.; Umemura, S.; Tachibana, K.; Manalo, A.H.; Riesz, P.: Sound waves and antineoplastic drugs: The possibility of an enhanced combined anticancer therapy. J.Med.Ultrasonics(Japan), 29, 173-187, 2002.3.Sostaric, J.Z. and Riesz, P.: Adsorption of surfactants at the gas/solution interface of cavitation bubbles: An ultrasound intensity independent frequency effect in sonochemistry. J. Phys. Chem. B., 106, 12537-12548, 2002.4.Miyoshi, N.; Sostaric, J.Z.; Riesz, P.: Correlation between sonochemistry of surfactant solutions and human leukemia cell killing by ultrasound and porphyrins. Free Rad. Biol. Med., 34, 710-719, 2003.

工作总结：声动力疗法是一种很有前途的新的癌症治疗方式，其基础是声增敏剂和超声联合作用杀死细胞的协同效应。超声波可以深入组织，并可以集中在肿瘤的一个小区域，以激活无毒分子（例如卟啉），从而最大限度地减少不良副作用。实验证据表明，声增敏是由于热塌陷空化气泡内部或附近的声增敏剂的化学活化，通过在水-气界面处的敏化剂的直接热解或由于水的热解形成的氢原子和羟基自由基的反应而形成敏化剂衍生的自由基。来自声敏剂的自由基（主要是碳中心的）与氧反应以形成过氧基和烷氧基自由基。与空化气泡内热解形成的OH自由基和H原子不同，超声波（47 kHz）与镓卟啉衍生物（ATX-70）协同作用对人白血病细胞的杀伤作用（HL-525和HL-60）悬浮在细胞培养基中进行了研究。有机表面活性剂优先积聚并随后在空化气泡的气/液界面处分解，产生可扩散到本体溶液的二次自由基。本研究中使用的镓卟啉类似物具有两个N-烷基侧链（ATX-Cx，其中x =碳原子数，范围从x = 2到x = 12）。通过改变正烷基链长度，从而改变ATX-Cx衍生物的表面活性剂性质，确定与ATX-Cx衍生物在空化气泡的气体/溶液界面处的积累相关的细胞杀伤。在ATX-Cx存在下超声分解后，观察到碳中心自由基的产率与细胞杀伤的强相关性。这些结果支持了声化学机制是负责超声和ATX-Cx对HL-525和HL-60细胞的协同作用的假设。超声诱导U937细胞凋亡和低渗介质裂解的研究支持了非致死性低渗可以增强超声诱导的细胞杀伤的假设。偶氮二（2-脒基丙烷）盐酸盐可增强超声对U937细胞的杀伤作用。这些研究结果表明，温度依赖性自由基发生器在超声治疗癌症的临床潜力。声动力学治疗的机制可能不是由一个普遍的机制决定的，而是可能受到多种因素的影响，包括生物模型的性质、声敏剂和超声参数。近藤，T.; Mori，H.; Zhao，Q.L.; Fukuda，S.; Riesz，P.：溶解气体对超声介导体外基因转染的影响。超声化学，9，197-203，2002.2.Feril，L.B.;近藤，T.; Umemura，S.; Tachibana，K.; Manalo，A.H.; Riesz，P.：声波和抗肿瘤药物：增强联合抗癌治疗的可能性。超声医学杂志（日本），29，173-187，2002.3. Sostaric，J.Z. Riesz，P.：表面活性剂在空化气泡气/液界面的吸附：声化学中与超声强度无关的频率效应。物理化学杂志B，106，12537-12548，2002.4. Miyoshi，N.; Sostaric，J.Z.; Riesz，P.：表面活性剂溶液的声化学与超声波和卟啉杀伤人白血病细胞的相关性。自由拉德。生物医学，34，710-719，2003.