碘化油磁流體納米顆粒的制備及其在腫瘤熱療中的應(yīng)用
發(fā)布時間：2018-08-22 19:47
【摘要】：腫瘤組織對高溫的敏感性比正常細胞高,因此和正常細胞相比,對溫度的耐受程度差。熱療便是根據(jù)這一特點,通過加熱使局部溫度升高來殺死癌細胞,目前已成為一種非常重要的腫瘤治療方法。磁流體熱療因為在治療的過程中對人體損傷小,有非常好的靶向性,既可以單獨用于腫瘤治療,也可以與其他的治療方式結(jié)合以實現(xiàn)協(xié)同效應(yīng),因此成為腫瘤熱療中的研究重點。碘化油是一種肝癌治療用栓塞劑,但碘化油自身僅能起到栓塞作用,因此需要和其他腫瘤治療方法結(jié)合使用以提高治療效果。將具有磁熱效應(yīng)的納米Fe304顆粒(MNPs)和碘化油結(jié)合,制備成Fe304/碘化油磁流體,磁流體有望在碘化油的作用下,在肝臟部位選擇性的沉積,長時間滯留,實現(xiàn)動脈栓塞熱療,對腫瘤特別是肝癌的治療有非常重要的實用價值。Fe304毒性小,穩(wěn)定性好,磁性能優(yōu)良,是最常用于制備磁流體的磁性材料。為了實現(xiàn)在腫瘤中的有效熱療,要求制備的Fe304具有高產(chǎn)熱性和生物相容性。另一方面,為了使Fe3O4/化油磁流體能夠長期穩(wěn)定存在,需要Fe304能夠均勻穩(wěn)定地分散在碘化油中。碘化油是一種油性試劑,因此對親水性的Fe3O4要進行表面改性,但改性方法存在過程復(fù)雜,容易引入雜質(zhì),磁性能降低的缺點。而目前制備疏水性Fe304的方法則存在反應(yīng)溫度較高等問題,影響了Fe304的應(yīng)用。本文針對上述問題,使用油胺作為溶劑、還原劑和表面改性劑,通過溶劑熱法在比較低的溫度下一步合成了具有高比飽和磁化強度的疏水性納米Fe3O4,對不同反應(yīng)物、溶劑和添加劑的影響進行了研究,使用XRD、SEM、 VSM等測試方法對產(chǎn)物的物相、形貌和性能等進行了分析。在此基礎(chǔ)上,將制備出的MNPs分散在碘化油中,制備出穩(wěn)定性好,SAR值高的Fe3O4/碘化油磁流體,并將其應(yīng)用于腫瘤熱療中。本文的主要研究內(nèi)容為：(1)有機鐵鹽Fe(acac)3為研究對象,對不同溶劑,反應(yīng)時間和添加劑合成的產(chǎn)物進行研究,獲得疏水性的MNPs。5m L苯醚和20mL油胺為反應(yīng)溶劑,200℃下反應(yīng)9h后得到疏水性MNPs,比飽和磁化強度為48emu/g。10mL油胺和10mL乙二醇為反應(yīng)溶劑,200℃下反應(yīng)8h制備出疏水性MNPs,產(chǎn)物的純度高,結(jié)晶性能好,比飽和磁化強度最高為768emu/ g。添加劑硬脂酸和油酸可以促進晶粒的生長,提高產(chǎn)物的結(jié)晶性能,但由于添加劑的包裹,MNPs的磁性能出現(xiàn)了不同程度的降低。(2)對無機鐵鹽在乙二醇和油胺溶劑中合成的MNPs進行了研究。研究結(jié)果顯示,FeCl3·6H2O為前驅(qū)體在200℃反應(yīng)8h得到的MNPs,結(jié)晶性能好,接近于球形,比飽和磁化強度高達90emu/g,具有良好的疏水性。該制備方法在比較低的溫度下進行,成本低,設(shè)備簡單,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+濃度,添加劑等因素的影響。油胺的含量越多,顆粒的粒徑越小,通過增加乙二醇的含量,可以獲得空心結(jié)構(gòu)的MNP s。Fe3+濃度的變化會改變顆粒的尺寸,進一步影響到磁性能。油酸能夠使MNPs的單晶結(jié)構(gòu)轉(zhuǎn)變?yōu)閳F簇狀結(jié)構(gòu)。硬脂酸能夠抑制顆粒的生長,加入量為1mmol時,MNPs的平均粒徑從71.38nm減小到41.73nm。(3)對Fe304的制備和生長機理進行了探討,Fe304的生成主要是基于油胺的還原作用,苯醚或乙二醇為重要的補充劑,不同形貌Fe304顆粒的生長機理不同,根據(jù)形貌的不同可以分為奧斯瓦爾德熟化,氣體形成的軟模板以及顆粒的自組裝。(4)將不同形貌,尺寸和磁性能的MNPs試樣分散在碘化油中,制備MNPs/碘化油磁流體,對其穩(wěn)定性進行評價。結(jié)果顯示,磁流體的穩(wěn)定性主要受顆粒形貌和大小的影響。以3mmolFeCl3·6H2O,10mL油胺, 10mL乙二醇和0.8mmol硬脂酸制備的產(chǎn)物的穩(wěn)定性最好,在碘化油中穩(wěn)定懸浮長達30天。對不同磁流體在交變磁場中的產(chǎn)熱情況進行研究,磁流體的SAR值最高可以達到117.8W/g,能夠?qū)崿F(xiàn)快速升溫,MNPs的比飽和磁化強度是影響SAR值的重要因素,但不是唯一的影響因子。研究了MNPs含量和電流強度對磁流體磁熱效應(yīng)的影響,通過MNPs的熱耗散機理,磁流體的能量耗散P與磁場強度和頻率成正比關(guān)系,當(dāng)顆粒尺寸大于17nm時,P值與尺寸的變化成反比,因此尺寸也同樣是影響SAR的一個因素。(5)采用直接接觸法對MNPs的細胞毒性進行評價,MNPs的濃度濃度越低,對細胞的毒性越弱。MNPs/碘化油磁流體注射到裸鼠的腋下腫瘤位置,在電流60A的交變磁場中進行磁熱療,磁流體具有較好的磁熱效應(yīng),腫瘤處溫度可以達到熱療溫度42℃以上,腫瘤細胞明顯凋亡。熱療對周圍組織沒有影響,具有局部熱療的效果。病理結(jié)果證實熱療后磁流體周圍的腫瘤細胞出現(xiàn)明顯壞死,碘化油的栓塞作用也引起了腫瘤細胞的死亡。磁流體長期使用過程中,裸鼠的心臟和肺部沒有明顯的組織病變,但肝臟部位有磁流體的沉積,顯示出磁流體能夠靶向地進入肝臟。
[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.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R730.5;TB383.1
，
本文編號：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.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R730.5;TB383.1
，
本文編號：2198130
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