中空Fe_3O_4微球作为磁性载体的实验研究
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摘要
作为肿瘤治疗药物的磁靶向载体,应既具有吸附能力,可以吸附足够的药物；同时又具有磁性,能在磁场作用下导向到靶部位,从而实现准确定位、提高药效、减轻毒副作用、缓慢释放的独特治疗效果。
本文主要研究中空Fe3O4微球载体的合成过程及其条件控制,以及该磁性载体的物理特性,尤其是脱吸附性及磁学特性,为进一步的载药研究提供物质和理论基础。文中用乳液聚合的方法,以苯乙烯(St)为单体,过硫酸铵(APS)为引发剂,十二烷基磺酸钠(SDS)为乳化剂,分步滴加KH-570制备直径在50-70nm左右活性PS乳胶粒,其后继续加入正硅酸乙酯(TEOS),使其与活性PS乳胶粒表面的硅羟基进行水解缩聚制得PS/SiO2核壳结构复合球(MPSi)。再采用在MPSi体系中先加入聚阳离子电解质聚二甲基二烯丙基氯化铵(PDADMAC),使其表面呈正电荷,从而吸附表面带有负电荷的磁流体,制备了PS/SiO2/Fe3O4 (MPSiFe)磁性复合球。最后将得到的磁性复合球在不同的温度下烧结去除PS内核,最终制得壳层结构完整的纳米中空Fe3O4微球。
本文中测定了中空Fe3O4微球载体物理性能(包括：粒径、BET比表面积、磁性能)及对阿霉素的吸附和脱附性能,研究中发现合成的中空Fe3O4微球呈明显的中空结构,孔直径为50nm左右,壳层厚度约为5nm,其结构完整,排列整齐,没有出现大面积坍塌的现象,而在500℃下烧结得到的磁性中空Fe3O4微球BET最大,为251.5570 m2/g。通过实验发现加入7%固含量为6%磁流体后得到纳米中空Fe3O4微球的磁性(Sm=37.63 emu／g)明显好于加入3%和5%磁流体的样品(Sm分别为11.27、13.54emu/g);中空Fe3O4微球载体对阿霉素吸附百分比为34.8%,同时在三小时的脱附实验中约85.8%药物能够缓慢释放。由此可见其同时具备较强的磁性和较好的吸附性能,能较好地兼顾其靶向性和载药性,适合作为药物载体用于肿瘤的磁靶向治疗,供作进一步研究。
本文研究以中空Fe3O4微球载体吸附同位素99mTcO4,将12只SD大鼠随机平均分为三组：99mTcO4水溶液组为经肝动脉注入1ml 99mTc04水溶液、未加磁场的99mTcO4-中空Fe3O4微球载体组为注入1ml标记99mTC中空Fe3O4微球悬液、加用磁场的99mTcO4-中空Fe3O4微球载体组为注入1m1标记99mTc中空Fe3O4微球悬液并予左肝表面放置脉冲磁场设置靶区；注药后5分钟、30分钟、1小时、2小时、3小时采用256×256矩阵进行SPECT全身显像,每次均采集300秒。通过观察同位素在不同的外加条件下在大鼠体内的分布,评估目标中空Fe3O4微球载体在体内分布及其发挥靶向治疗的可能效果。从而得到中空Fe3O4微球载体对99mTCO4具有良好的吸附性,加用脉冲磁场的99mTcO4中空Fe3O4微球载体可使靶区的放射计数明显增加,靶向组肝区的单位像素体外放射计数与本底的单位像素体外放射计数的比值明显高于其他组(P<0.05)；而且靶向组靶区左肝放射计数要高于右肝,其左右肝脏(靶区与非靶区)区域各时间段的单位像素放射计数与全身单位像素放射计数的比值的差值大于另外两组。同时也明显减少了在其他组织器官的含量(P<0.05),加用脉冲磁场后中空Fe3O4微球载体在肝脏局部浓度和停留时间增加的同时,明显减少了其在其他组织器官的含量,当其载药时可以增加靶区组织的有效作用浓度和作用时间,从而增加载药时在组织的有效作用浓度和作用时间；并可以达到减少非作用靶器官药物浓度,减少药物由此带来副作用和不良反应的可能性。
As a magnetic targeted carrier of cancer therapy drugs, both absorption capacity should be adequate absorption of drugs, but also a magnetic, in the magnetic field under the guidance to the target site, thus achieving accurate positioning, improve the efficacy and reduce side effects, The slow release of the unique therapeutic effect.
This paper studies the hollow nanospheres with Fe3O4 control of the process and its conditions, and the physical characteristics of the magnetic carrier, in particular from absorption and magnetic properties of the drug for further research to provide material and theoretical basis. Active polystyrene (PS) with silica hydroxyl end group was synthesized by emulsion polymerization of styrene in a mixture of water, using (NH4)2S2O4 (APS) as initiator, C12H25NaO4S (SDS) as emulsify agent. The diameter of active polystyrene spheres is 50-70nm. The PS/SiO2 organic-inorganic hybrid spheres (MPSi) were prepared by hydrolyzed tetraethoxysilane (TEOS) in condensation copolymerized with the-OH on the surface of active PS spheres. The result showed that the content of TEOS would greatly affect the thickness of SiO2 layer.
The magnetic PS/SiO2/Fe3O4 nanospheres were prepared by layer-by-layer self-assembly. The spheres were characterized by TEM, VSM, XRD etc. So PS/SiO2/Fe3O4 (MPSiFe) nanospheres were prepared by layer-by-layer (LbL) self-assembly. The effect of different Fe3O4 volume to the shape magnetic nanospheres was discussed. The hollow nanospheres with Fe3O4 were prepared by removing PS core in high temperature. And the effect of specific surface area in different temperature was discussed. At last, the diameter with 70-80nm hollow nanospheres with Fe3O4 was prepared.
To determine the physical characteritic including the morphology, stability, magnetic property, and the absorbable or desorbable ability to 99mTc of Hollow Nanospheres with Fe3O4. The Hollow Nanospheres with Fe3O4 had the better powerful magnetism and the better absorbable ability. It is suitable for the further research.
The hollow nanospheres with Fe3O4 absorbed radionuclide 99mTc04 and infused into body of SD mouse which were divided randomly into three groups under the magnetic fields or not. infused different solution through common hepatic artery, which was water solution of 99mTcO4, or the hollow nanospheres with Fe3O4 absorbed 99mTcO4. The group which infused into the hollow nanospheres with Fe3O4 absorbed 99mTc04 under magnetic fields or not.5minuets,30 minuets, lhour,2hours, and 3hours after injection, collected the imagines by SPECT, each inspected duration lasted 300 seconds.We can results the hollow nanospheres with Fe3O4 had satisfactory absorbable ability with 99mTeO4, under magnetic fields, the radioactivity counts of targeted organ was obviously increased (P<0.05), but greatly decreased in other organs (P<0.05). So it concluted that the hollow nanospheres with Fe3O4 conbined with favorable targeted characterization.
本文主要研究中空Fe3O4微球载体的合成过程及其条件控制,以及该磁性载体的物理特性,尤其是脱吸附性及磁学特性,为进一步的载药研究提供物质和理论基础。文中用乳液聚合的方法,以苯乙烯(St)为单体,过硫酸铵(APS)为引发剂,十二烷基磺酸钠(SDS)为乳化剂,分步滴加KH-570制备直径在50-70nm左右活性PS乳胶粒,其后继续加入正硅酸乙酯(TEOS),使其与活性PS乳胶粒表面的硅羟基进行水解缩聚制得PS/SiO2核壳结构复合球(MPSi)。再采用在MPSi体系中先加入聚阳离子电解质聚二甲基二烯丙基氯化铵(PDADMAC),使其表面呈正电荷,从而吸附表面带有负电荷的磁流体,制备了PS/SiO2/Fe3O4 (MPSiFe)磁性复合球。最后将得到的磁性复合球在不同的温度下烧结去除PS内核,最终制得壳层结构完整的纳米中空Fe3O4微球。
本文中测定了中空Fe3O4微球载体物理性能(包括：粒径、BET比表面积、磁性能)及对阿霉素的吸附和脱附性能,研究中发现合成的中空Fe3O4微球呈明显的中空结构,孔直径为50nm左右,壳层厚度约为5nm,其结构完整,排列整齐,没有出现大面积坍塌的现象,而在500℃下烧结得到的磁性中空Fe3O4微球BET最大,为251.5570 m2/g。通过实验发现加入7%固含量为6%磁流体后得到纳米中空Fe3O4微球的磁性(Sm=37.63 emu／g)明显好于加入3%和5%磁流体的样品(Sm分别为11.27、13.54emu/g);中空Fe3O4微球载体对阿霉素吸附百分比为34.8%,同时在三小时的脱附实验中约85.8%药物能够缓慢释放。由此可见其同时具备较强的磁性和较好的吸附性能,能较好地兼顾其靶向性和载药性,适合作为药物载体用于肿瘤的磁靶向治疗,供作进一步研究。
本文研究以中空Fe3O4微球载体吸附同位素99mTcO4,将12只SD大鼠随机平均分为三组：99mTcO4水溶液组为经肝动脉注入1ml 99mTc04水溶液、未加磁场的99mTcO4-中空Fe3O4微球载体组为注入1ml标记99mTC中空Fe3O4微球悬液、加用磁场的99mTcO4-中空Fe3O4微球载体组为注入1m1标记99mTc中空Fe3O4微球悬液并予左肝表面放置脉冲磁场设置靶区；注药后5分钟、30分钟、1小时、2小时、3小时采用256×256矩阵进行SPECT全身显像,每次均采集300秒。通过观察同位素在不同的外加条件下在大鼠体内的分布,评估目标中空Fe3O4微球载体在体内分布及其发挥靶向治疗的可能效果。从而得到中空Fe3O4微球载体对99mTCO4具有良好的吸附性,加用脉冲磁场的99mTcO4中空Fe3O4微球载体可使靶区的放射计数明显增加,靶向组肝区的单位像素体外放射计数与本底的单位像素体外放射计数的比值明显高于其他组(P<0.05)；而且靶向组靶区左肝放射计数要高于右肝,其左右肝脏(靶区与非靶区)区域各时间段的单位像素放射计数与全身单位像素放射计数的比值的差值大于另外两组。同时也明显减少了在其他组织器官的含量(P<0.05),加用脉冲磁场后中空Fe3O4微球载体在肝脏局部浓度和停留时间增加的同时,明显减少了其在其他组织器官的含量,当其载药时可以增加靶区组织的有效作用浓度和作用时间,从而增加载药时在组织的有效作用浓度和作用时间；并可以达到减少非作用靶器官药物浓度,减少药物由此带来副作用和不良反应的可能性。
As a magnetic targeted carrier of cancer therapy drugs, both absorption capacity should be adequate absorption of drugs, but also a magnetic, in the magnetic field under the guidance to the target site, thus achieving accurate positioning, improve the efficacy and reduce side effects, The slow release of the unique therapeutic effect.
This paper studies the hollow nanospheres with Fe3O4 control of the process and its conditions, and the physical characteristics of the magnetic carrier, in particular from absorption and magnetic properties of the drug for further research to provide material and theoretical basis. Active polystyrene (PS) with silica hydroxyl end group was synthesized by emulsion polymerization of styrene in a mixture of water, using (NH4)2S2O4 (APS) as initiator, C12H25NaO4S (SDS) as emulsify agent. The diameter of active polystyrene spheres is 50-70nm. The PS/SiO2 organic-inorganic hybrid spheres (MPSi) were prepared by hydrolyzed tetraethoxysilane (TEOS) in condensation copolymerized with the-OH on the surface of active PS spheres. The result showed that the content of TEOS would greatly affect the thickness of SiO2 layer.
The magnetic PS/SiO2/Fe3O4 nanospheres were prepared by layer-by-layer self-assembly. The spheres were characterized by TEM, VSM, XRD etc. So PS/SiO2/Fe3O4 (MPSiFe) nanospheres were prepared by layer-by-layer (LbL) self-assembly. The effect of different Fe3O4 volume to the shape magnetic nanospheres was discussed. The hollow nanospheres with Fe3O4 were prepared by removing PS core in high temperature. And the effect of specific surface area in different temperature was discussed. At last, the diameter with 70-80nm hollow nanospheres with Fe3O4 was prepared.
To determine the physical characteritic including the morphology, stability, magnetic property, and the absorbable or desorbable ability to 99mTc of Hollow Nanospheres with Fe3O4. The Hollow Nanospheres with Fe3O4 had the better powerful magnetism and the better absorbable ability. It is suitable for the further research.
The hollow nanospheres with Fe3O4 absorbed radionuclide 99mTc04 and infused into body of SD mouse which were divided randomly into three groups under the magnetic fields or not. infused different solution through common hepatic artery, which was water solution of 99mTcO4, or the hollow nanospheres with Fe3O4 absorbed 99mTcO4. The group which infused into the hollow nanospheres with Fe3O4 absorbed 99mTc04 under magnetic fields or not.5minuets,30 minuets, lhour,2hours, and 3hours after injection, collected the imagines by SPECT, each inspected duration lasted 300 seconds.We can results the hollow nanospheres with Fe3O4 had satisfactory absorbable ability with 99mTeO4, under magnetic fields, the radioactivity counts of targeted organ was obviously increased (P<0.05), but greatly decreased in other organs (P<0.05). So it concluted that the hollow nanospheres with Fe3O4 conbined with favorable targeted characterization.
引文
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[2]Varmus H. The new era in cancer research [J]. Science,2006,312 (5777) 1162-1165
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