碘化油磁流体纳米颗粒的制备及其在肿瘤热疗中的应用
发布时间：2018-08-22 19:47
【摘要】：肿瘤组织对高温的敏感性比正常细胞高,因此和正常细胞相比,对温度的耐受程度差。热疗便是根据这一特点,通过加热使局部温度升高来杀死癌细胞,目前已成为一种非常重要的肿瘤治疗方法。磁流体热疗因为在治疗的过程中对人体损伤小,有非常好的靶向性,既可以单独用于肿瘤治疗,也可以与其他的治疗方式结合以实现协同效应,因此成为肿瘤热疗中的研究重点。碘化油是一种肝癌治疗用栓塞剂,但碘化油自身仅能起到栓塞作用,因此需要和其他肿瘤治疗方法结合使用以提高治疗效果。将具有磁热效应的纳米Fe304颗粒(MNPs)和碘化油结合,制备成Fe304/碘化油磁流体,磁流体有望在碘化油的作用下,在肝脏部位选择性的沉积,长时间滞留,实现动脉栓塞热疗,对肿瘤特别是肝癌的治疗有非常重要的实用价值。Fe304毒性小,稳定性好,磁性能优良,是最常用于制备磁流体的磁性材料。为了实现在肿瘤中的有效热疗,要求制备的Fe304具有高产热性和生物相容性。另一方面,为了使Fe3O4/化油磁流体能够长期稳定存在,需要Fe304能够均匀稳定地分散在碘化油中。碘化油是一种油性试剂,因此对亲水性的Fe3O4要进行表面改性,但改性方法存在过程复杂,容易引入杂质,磁性能降低的缺点。而目前制备疏水性Fe304的方法则存在反应温度较高等问题,影响了Fe304的应用。本文针对上述问题,使用油胺作为溶剂、还原剂和表面改性剂,通过溶剂热法在比较低的温度下一步合成了具有高比饱和磁化强度的疏水性纳米Fe3O4,对不同反应物、溶剂和添加剂的影响进行了研究,使用XRD、SEM、 VSM等测试方法对产物的物相、形貌和性能等进行了分析。在此基础上,将制备出的MNPs分散在碘化油中,制备出稳定性好,SAR值高的Fe3O4/碘化油磁流体,并将其应用于肿瘤热疗中。本文的主要研究内容为：(1)有机铁盐Fe(acac)3为研究对象,对不同溶剂,反应时间和添加剂合成的产物进行研究,获得疏水性的MNPs。5m L苯醚和20mL油胺为反应溶剂,200℃下反应9h后得到疏水性MNPs,比饱和磁化强度为48emu/g。10mL油胺和10mL乙二醇为反应溶剂,200℃下反应8h制备出疏水性MNPs,产物的纯度高,结晶性能好,比饱和磁化强度最高为768emu/ g。添加剂硬脂酸和油酸可以促进晶粒的生长,提高产物的结晶性能,但由于添加剂的包裹,MNPs的磁性能出现了不同程度的降低。(2)对无机铁盐在乙二醇和油胺溶剂中合成的MNPs进行了研究。研究结果显示,FeCl3·6H2O为前驱体在200℃反应8h得到的MNPs,结晶性能好,接近于球形,比饱和磁化强度高达90emu/g,具有良好的疏水性。该制备方法在比较低的温度下进行,成本低,设备简单,避免了二次改性所造成的污染和磁性能的降低。MNPs的形貌,尺寸和磁性能受油胺和乙二醇比值,Fe3+浓度,添加剂等因素的影响。油胺的含量越多,颗粒的粒径越小,通过增加乙二醇的含量,可以获得空心结构的MNP s。Fe3+浓度的变化会改变颗粒的尺寸,进一步影响到磁性能。油酸能够使MNPs的单晶结构转变为团簇状结构。硬脂酸能够抑制颗粒的生长,加入量为1mmol时,MNPs的平均粒径从71.38nm减小到41.73nm。(3)对Fe304的制备和生长机理进行了探讨,Fe304的生成主要是基于油胺的还原作用,苯醚或乙二醇为重要的补充剂,不同形貌Fe304颗粒的生长机理不同,根据形貌的不同可以分为奥斯瓦尔德熟化,气体形成的软模板以及颗粒的自组装。(4)将不同形貌,尺寸和磁性能的MNPs试样分散在碘化油中,制备MNPs/碘化油磁流体,对其稳定性进行评价。结果显示,磁流体的稳定性主要受颗粒形貌和大小的影响。以3mmolFeCl3·6H2O,10mL油胺, 10mL乙二醇和0.8mmol硬脂酸制备的产物的稳定性最好,在碘化油中稳定悬浮长达30天。对不同磁流体在交变磁场中的产热情况进行研究,磁流体的SAR值最高可以达到117.8W/g,能够实现快速升温,MNPs的比饱和磁化强度是影响SAR值的重要因素,但不是唯一的影响因子。研究了MNPs含量和电流强度对磁流体磁热效应的影响,通过MNPs的热耗散机理,磁流体的能量耗散P与磁场强度和频率成正比关系,当颗粒尺寸大于17nm时,P值与尺寸的变化成反比,因此尺寸也同样是影响SAR的一个因素。(5)采用直接接触法对MNPs的细胞毒性进行评价,MNPs的浓度浓度越低,对细胞的毒性越弱。MNPs/碘化油磁流体注射到裸鼠的腋下肿瘤位置,在电流60A的交变磁场中进行磁热疗,磁流体具有较好的磁热效应,肿瘤处温度可以达到热疗温度42℃以上,肿瘤细胞明显凋亡。热疗对周围组织没有影响,具有局部热疗的效果。病理结果证实热疗后磁流体周围的肿瘤细胞出现明显坏死,碘化油的栓塞作用也引起了肿瘤细胞的死亡。磁流体长期使用过程中,裸鼠的心脏和肺部没有明显的组织病变,但肝脏部位有磁流体的沉积,显示出磁流体能够靶向地进入肝脏。
[Abstract]:Tumor tissue is more sensitive to high temperature than normal cells, so it is less tolerant to temperature than normal cells. Thermotherapy is based on this feature, by heating the local temperature to kill cancer cells, has become a very important method of cancer treatment. Lipiodol is a kind of embolic agent for the treatment of hepatocellular carcinoma, but lipiodol itself can only play an embolic role, so it is necessary to treat other tumors with other methods. Fe304/iodized oil magnetic fluid was prepared by the combination of nano-Fe304 particles (MNPs) with iodized oil. The magnetic fluid is expected to deposit selectively in the liver site under the action of iodized oil, and remain for a long time. It is very important to achieve arterial embolization hyperthermia for the treatment of tumor, especially liver cancer. Fe304 has low toxicity, good stability and excellent magnetic properties. Fe304 is the most commonly used magnetic material for the preparation of magnetic fluids. In order to achieve effective hyperthermia in tumors, the preparation of Fe304 is required to have high heat production and biocompatibility. On the other hand, in order to make Fe3O4 / chemical oil magnetic fluids can exist for a long time, Fe304 is required to be uniform and stable. Iodized oil is an oily reagent, so the surface modification of hydrophilic Fe3O4 is necessary. However, the modification method has the disadvantages of complex process, easy introduction of impurities, and low magnetic properties. Hydrophobic nano-Fe_3O_4 with high saturation magnetization was synthesized by solvothermal method at lower temperature using oleamine as solvent, reductant and surface modifier. The effects of different reactants, solvents and additives on the phase, morphology and properties of the product were studied by XRD, SEM and VSM. On this basis, the prepared MNPs were dispersed in iodized oil to prepare Fe3O4/iodized oil magnetic fluid with good stability and high SAR value, and applied to tumor hyperthermia. The main research contents of this paper are as follows: (1) Organic ferric salt Fe (acac) 3 was synthesized with different solvents, reaction time and additives. Hydrophobic MNPs were prepared by the reaction of hydrophobic MNPs.5mL phenyl ether and 20 mL oleamine in the solvent. Hydrophobic MNPs were obtained by the reaction at 200 C for 9 h. The specific saturation magnetization was 48 emu/g.10mL oleamine and 10 mL ethylene glycol were used as the reaction solvent. Hydrophobic MNPs were prepared at 200 C for 8 h with high purity, good crystallinity and the highest specific saturation magnetization. The addition of stearic acid and oleic acid to 768 emu/g. can promote the growth of grains and improve the crystallinity of products, but the magnetic properties of MNPs decrease in varying degrees due to the encapsulation of additives. (2) The synthesis of MNPs by inorganic ferric salts in ethylene glycol and oleamine solvent was studied. The results showed that FeCl3.6H2O was the precursor at 200 C. The MNPs obtained after 8 h reaction have good crystallinity, close to spherical shape, high specific saturation magnetization of 90 emu/g and good hydrophobicity. The preparation method is carried out at a relatively low temperature, low cost, simple equipment, avoiding pollution caused by secondary modification and reducing magnetic properties. The morphology, size and magnetic properties of MNPs are subject to oleamine and ethylene glycol. The larger the content of oleamine, the smaller the particle size. By increasing the content of ethylene glycol, the hollow MNP s. Fe3+ can change the size of the particles and further affect the magnetic properties. The average particle size of MNPs decreased from 71.38 nm to 41.73 nm when adding 1 mmol. (3) The preparation and growth mechanism of Fe304 were discussed. The formation of Fe304 was mainly based on the reduction of oleamine, and the growth mechanism of Fe304 particles with different morphologies was different, depending on the morphology. (4) MNPs with different morphologies, sizes and magnetic properties were dispersed in iodized oil to prepare MNPs/iodized oil magnetic fluid and evaluate its stability. The products prepared by eCl3.6H2O, 10mL oleamine, 10mL ethylene glycol and 0.8mmol stearic acid have the best stability and can be suspended stably in iodized oil for 30 days. The influence of MNPs content and current intensity on the magneto-thermal effect of MNPs is studied. Through the heat dissipation mechanism of MNPs, the energy dissipation P of MNPs is proportional to the magnetic field intensity and frequency. When the particle size is larger than 17 nm, the P value is inversely proportional to the size change, so the size is the same. (5) The cytotoxicity of MNPs was evaluated by direct contact method. The lower the concentration of MNPs, the weaker the cytotoxicity of MNPs. MNPs/lipiodol magnetic fluid was injected into the axillary tumor of nude mice. Hyperthermia has no effect on the surrounding tissues and has the effect of local hyperthermia. Pathological results show that the tumor cells around the magnetic fluid show obvious necrosis after hyperthermia, and the embolization of iodized oil also causes the death of tumor cells. During the long-term use of the magnetic fluid, the heart of nude mice is damaged. There were no significant histopathological changes in the lungs and viscera, but there were deposits of magnetic fluids in the liver, indicating that magnetic fluids could target the liver.
【学位授予单位】：山东大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R730.5;TB383.1
，
本文编号：2198130
[Abstract]:Tumor tissue is more sensitive to high temperature than normal cells, so it is less tolerant to temperature than normal cells. Thermotherapy is based on this feature, by heating the local temperature to kill cancer cells, has become a very important method of cancer treatment. Lipiodol is a kind of embolic agent for the treatment of hepatocellular carcinoma, but lipiodol itself can only play an embolic role, so it is necessary to treat other tumors with other methods. Fe304/iodized oil magnetic fluid was prepared by the combination of nano-Fe304 particles (MNPs) with iodized oil. The magnetic fluid is expected to deposit selectively in the liver site under the action of iodized oil, and remain for a long time. It is very important to achieve arterial embolization hyperthermia for the treatment of tumor, especially liver cancer. Fe304 has low toxicity, good stability and excellent magnetic properties. Fe304 is the most commonly used magnetic material for the preparation of magnetic fluids. In order to achieve effective hyperthermia in tumors, the preparation of Fe304 is required to have high heat production and biocompatibility. On the other hand, in order to make Fe3O4 / chemical oil magnetic fluids can exist for a long time, Fe304 is required to be uniform and stable. Iodized oil is an oily reagent, so the surface modification of hydrophilic Fe3O4 is necessary. However, the modification method has the disadvantages of complex process, easy introduction of impurities, and low magnetic properties. Hydrophobic nano-Fe_3O_4 with high saturation magnetization was synthesized by solvothermal method at lower temperature using oleamine as solvent, reductant and surface modifier. The effects of different reactants, solvents and additives on the phase, morphology and properties of the product were studied by XRD, SEM and VSM. On this basis, the prepared MNPs were dispersed in iodized oil to prepare Fe3O4/iodized oil magnetic fluid with good stability and high SAR value, and applied to tumor hyperthermia. The main research contents of this paper are as follows: (1) Organic ferric salt Fe (acac) 3 was synthesized with different solvents, reaction time and additives. Hydrophobic MNPs were prepared by the reaction of hydrophobic MNPs.5mL phenyl ether and 20 mL oleamine in the solvent. Hydrophobic MNPs were obtained by the reaction at 200 C for 9 h. The specific saturation magnetization was 48 emu/g.10mL oleamine and 10 mL ethylene glycol were used as the reaction solvent. Hydrophobic MNPs were prepared at 200 C for 8 h with high purity, good crystallinity and the highest specific saturation magnetization. The addition of stearic acid and oleic acid to 768 emu/g. can promote the growth of grains and improve the crystallinity of products, but the magnetic properties of MNPs decrease in varying degrees due to the encapsulation of additives. (2) The synthesis of MNPs by inorganic ferric salts in ethylene glycol and oleamine solvent was studied. The results showed that FeCl3.6H2O was the precursor at 200 C. The MNPs obtained after 8 h reaction have good crystallinity, close to spherical shape, high specific saturation magnetization of 90 emu/g and good hydrophobicity. The preparation method is carried out at a relatively low temperature, low cost, simple equipment, avoiding pollution caused by secondary modification and reducing magnetic properties. The morphology, size and magnetic properties of MNPs are subject to oleamine and ethylene glycol. The larger the content of oleamine, the smaller the particle size. By increasing the content of ethylene glycol, the hollow MNP s. Fe3+ can change the size of the particles and further affect the magnetic properties. The average particle size of MNPs decreased from 71.38 nm to 41.73 nm when adding 1 mmol. (3) The preparation and growth mechanism of Fe304 were discussed. The formation of Fe304 was mainly based on the reduction of oleamine, and the growth mechanism of Fe304 particles with different morphologies was different, depending on the morphology. (4) MNPs with different morphologies, sizes and magnetic properties were dispersed in iodized oil to prepare MNPs/iodized oil magnetic fluid and evaluate its stability. The products prepared by eCl3.6H2O, 10mL oleamine, 10mL ethylene glycol and 0.8mmol stearic acid have the best stability and can be suspended stably in iodized oil for 30 days. The influence of MNPs content and current intensity on the magneto-thermal effect of MNPs is studied. Through the heat dissipation mechanism of MNPs, the energy dissipation P of MNPs is proportional to the magnetic field intensity and frequency. When the particle size is larger than 17 nm, the P value is inversely proportional to the size change, so the size is the same. (5) The cytotoxicity of MNPs was evaluated by direct contact method. The lower the concentration of MNPs, the weaker the cytotoxicity of MNPs. MNPs/lipiodol magnetic fluid was injected into the axillary tumor of nude mice. Hyperthermia has no effect on the surrounding tissues and has the effect of local hyperthermia. Pathological results show that the tumor cells around the magnetic fluid show obvious necrosis after hyperthermia, and the embolization of iodized oil also causes the death of tumor cells. During the long-term use of the magnetic fluid, the heart of nude mice is damaged. There were no significant histopathological changes in the lungs and viscera, but there were deposits of magnetic fluids in the liver, indicating that magnetic fluids could target the liver.
【学位授予单位】：山东大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R730.5;TB383.1
，
本文编号：2198130
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