超小型超顺磁性磁共振对比剂的制备及性能研究
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摘要
近年来,由于其特殊性能,纳米磁性材料越来越多地应用到生物技术和生物医学工程方面,如磁分离、靶向药物和磁共振对比剂等等。目前对于磁共振检测来说,30%都需要磁共振对比剂来提高信号的对比度,因此制备研究新型的磁共振对比剂具有很重要的科学意义和医疗诊断价值。
我们在共沉淀法的基础上制备出了一种超小型超顺磁性氧化铁磁共振对比剂—纳米氧化铁粒子为核心,外面包裹高聚物。作为超小型超顺磁性磁共振对比剂,样品必须稳定性及分散性好,粒子粒径在10纳米以下。如何使纳米粒子有良好的分散性一直是纳米材料领域的热点问题之一,我们最终选用具有生物相容性、可降解、亲水性长链高聚物葡聚糖作为稳定剂包覆氧化铁纳米粒子,得到了分散性良好的可作为磁共振对比剂的稳定的磁流体。在实验过程中发现,葡聚糖加入量的多少决定样品是否形成稳定的胶体。
超顺磁性是超小型超顺磁性磁共振对比剂的另一个必要条件。我们对同一样品的磁性能进行了两次测量,中间时间间隔为6个月。两次测量结果显示,两次测量均显示了超顺磁性,且饱和磁化强度相差不大,原因是葡聚糖包覆材料对氧化铁的磁稳定性起了很大作用。此外,我们还通过粘度仪、热分析和红外光谱对样品粘度、热稳定性和表面包覆情况进行了研究。
最后,为了验证我们所作样品作为磁共振对比剂的效果,我们进行了动物肝脏的磁共振成像实验,结果表明,我们所制备的样品对成像信号有明显的增强效果,是一种很有前途的磁共振对比剂-超小型超顺磁性氧化铁磁共振对比剂。
In recent years,because of its special properties, nano-material has been wildly applied to various aspects in biotechnology and biomedical engineering, such as magnetic separation, target drug and magnetic resonance imaging (MRI) contrast agent, et al. Currently, about one-third of MRI scans are in need of administration of a contrast agent to improve the contrast of signals. Therefore, it is of great scientific significance and diagnostic value to synthesize and study new types of MRI contrast agent.
Based on the method of co-precipitation, we synthesized a kind of ultrasmall superparamagnetic iron oxide (USPIO) MRI contrast agent—nanosized iron-oxide particles surrounded by polymer. To be as USPIO MRI contrast agent, the sample must be stable, well dispersed and the diameter of the particles must be no more than 10 nm. How to get well-dispersed nanopartilces has always been one of the intense researches in the area of nanomaterial. We at last chose the polymer dextran which is biocompatible, biodegradable and hydrophilic as the coating material and get magnetic fluid in well dispersed state which can be used as MRI contrast agent. It is found that the quantity of the dextran is a major factor for the formation of stable colloid.
Superparamagnetism is another indispensable property to USPIO contrast agent. We conducted magnetic measurements in two different times to the same sample. The period between the two measurements is about six months. The two results manifested both measurements have superparamagnetism and there is not much difference in the saturation magnetization. It is the coating material dextran that improved the magnetic stability. Moreover, we also studied the properties of viscidity,thermostability and surface.
At last, to test the effect of our sample to be as MRI contrast agent, we conducted MRI experiments in animal liver. The results indicate that the sample we synthesized can greatly improve the signal contrast and can be a good candidate for MRI contrast agent-USPIO MRI contrast agent.
我们在共沉淀法的基础上制备出了一种超小型超顺磁性氧化铁磁共振对比剂—纳米氧化铁粒子为核心,外面包裹高聚物。作为超小型超顺磁性磁共振对比剂,样品必须稳定性及分散性好,粒子粒径在10纳米以下。如何使纳米粒子有良好的分散性一直是纳米材料领域的热点问题之一,我们最终选用具有生物相容性、可降解、亲水性长链高聚物葡聚糖作为稳定剂包覆氧化铁纳米粒子,得到了分散性良好的可作为磁共振对比剂的稳定的磁流体。在实验过程中发现,葡聚糖加入量的多少决定样品是否形成稳定的胶体。
超顺磁性是超小型超顺磁性磁共振对比剂的另一个必要条件。我们对同一样品的磁性能进行了两次测量,中间时间间隔为6个月。两次测量结果显示,两次测量均显示了超顺磁性,且饱和磁化强度相差不大,原因是葡聚糖包覆材料对氧化铁的磁稳定性起了很大作用。此外,我们还通过粘度仪、热分析和红外光谱对样品粘度、热稳定性和表面包覆情况进行了研究。
最后,为了验证我们所作样品作为磁共振对比剂的效果,我们进行了动物肝脏的磁共振成像实验,结果表明,我们所制备的样品对成像信号有明显的增强效果,是一种很有前途的磁共振对比剂-超小型超顺磁性氧化铁磁共振对比剂。
In recent years,because of its special properties, nano-material has been wildly applied to various aspects in biotechnology and biomedical engineering, such as magnetic separation, target drug and magnetic resonance imaging (MRI) contrast agent, et al. Currently, about one-third of MRI scans are in need of administration of a contrast agent to improve the contrast of signals. Therefore, it is of great scientific significance and diagnostic value to synthesize and study new types of MRI contrast agent.
Based on the method of co-precipitation, we synthesized a kind of ultrasmall superparamagnetic iron oxide (USPIO) MRI contrast agent—nanosized iron-oxide particles surrounded by polymer. To be as USPIO MRI contrast agent, the sample must be stable, well dispersed and the diameter of the particles must be no more than 10 nm. How to get well-dispersed nanopartilces has always been one of the intense researches in the area of nanomaterial. We at last chose the polymer dextran which is biocompatible, biodegradable and hydrophilic as the coating material and get magnetic fluid in well dispersed state which can be used as MRI contrast agent. It is found that the quantity of the dextran is a major factor for the formation of stable colloid.
Superparamagnetism is another indispensable property to USPIO contrast agent. We conducted magnetic measurements in two different times to the same sample. The period between the two measurements is about six months. The two results manifested both measurements have superparamagnetism and there is not much difference in the saturation magnetization. It is the coating material dextran that improved the magnetic stability. Moreover, we also studied the properties of viscidity,thermostability and surface.
At last, to test the effect of our sample to be as MRI contrast agent, we conducted MRI experiments in animal liver. The results indicate that the sample we synthesized can greatly improve the signal contrast and can be a good candidate for MRI contrast agent-USPIO MRI contrast agent.
引文
[1] 白木,周洁. 纳米磁性材料及其应用.信息记录材料.(2002).3(2):38-39
[2] Junu Chatterjee, Yousef Haik, Ching-Jen Chen. Polythylene magnetic nanoparticle: a new magnetic material for biomedical applications. JMMM. 2002.246: 382-391
[3] R.S.Molday and L.L.Molday Separation of cells labeled with immunonspecific iron dextran microspheres using high magnetic chromatography. FEBS. 1984.170(2): 232-237
[4] N.Cem Balci, Mustafa Sirvanci, Cihan Duran, et al., Hepatic adenomatosis MRI demonstration with the use of superparamagnetic iron oxide. Journal of Clinical Imaging 2002, 26: 35-38
[5] Maire-France Bellin.Catherine Beigelman.Sophie Precetti-Morel. Iron oxide-enhanced MR lymphography: initial experience.European Journal of Radiology. 2000.34: 257-264
[6] 董聿生,梁峰,余向阳等.新型磁性葡聚糖亲和吸附剂的制备及其在尿激酶纯化中的应用 色谱 2000.19(1):21-24
[7] Cavicchi R E, Silsbee R H. First steps towards tailoring fine and ultrafine iron particles using micromulsions. Phys. Rev. Lett. .1984.52(5): 1453-1457
[8] M Arturo Lopez-Quintela, Jose Rivas. Chemical reaction in microemulsions: a powerful method to obtain ultrafine particles. Langmuir, 1999, 154(4): 447-453
[9] Ball P, Garwin L. Matrix-mediated synthesis of nanocrystalline r-Fe2O3: a new optically transparent magnetic material. Nature, 1992, 355: 761-771
[10] 张立德,牟季美.纳米材料和纳米结构.第2版.北京:科学出版社,2001
[11] 李国栋.金属磁性功能材料进展.金属功能材料.1996.3(6):202-204
[12] 林培豪,曾中明.磁性材料进展.物理.2000.29(6):323-332
[13] 沈良,江国华.磁性纳米功能材料研究进展.杭州师范学院学报(自然科学版).2001.18(5):40-44
[14] 都有为,徐明祥,吴坚等.镍超微颗粒的磁性.物理学报.1992, 41(1): 149-154
[15] Lin C H, Shen Z W, Wang M L. et al., Hydrothermal processing to produce magnetic particles. IEEE Trans. Magn. 1990, 26(1):15-17
[16] F.E.Spada, E.J.Mcniff Jr., S. Foner, Anomalous properties of magnetic nanopartilces. JMMM. 1999, 196:591-594
[17] Y. Jin, C.L.Dennis, S.A.Majetich, Nanoscale characterization of magnetic nanoparticles. Nanostructured Materials.1999.12: 763-768
[18] 王晨 胡军 罗伟等 磁性液体的研究进展. 金属功能材料.2003.10(4):35-38
[19] 高善民,孙树声,刘兆明.纳米材料的应用前景展望.化学世界2000, 11: 613-616
[20] 许海燕,孔桦,杨子彬.纳米材料及其在生物医学工程中的应用. 国外医学生物医学工程分册.1998.21(5):262-266
[21] Ole Diettrich, Kevin Mills, Andrew W.Johnson, et al., Application of magnetic chromatography to the isolation of lysosomes from fibroblasts of patients with lysosomal storage disorders. FEBS Letters.1998.441:369-372
[22] 沈其丰.核磁共振碳谱.第1版.北京:北京大学出版社.1988. 1-3
[23] Jeff W.M. Bulte, Marcel de Cuyper, Daryl Despres, et al., Preparation, relaxometry, and biokinetcs of PEGylated magnetoliposomes as MR contrast agent. JMMM, 2000, 194: 204-209
[24] V.Rousseau, D.Pouliquen, F.Darcel, et al., NMR investigation of experimental chemical induced brain tumors in rats, potential of a superparamagnetic contrast agent(MD3) to improve diagnosis. Magnetic Resonance Materials in Biology, Physics and Medicine.1998.6:13-21
[25] D.Pouliguen, R.Perdrisot, A.Ermias, et al., Superparamagnetic iron oxide nanoparticls as a liver MRI contrast agent: contribution of microencapsulation to improved biodistribution.Magnetic Resonance Imaging.1989.7: 619-627
[26] Yi-Xiang J.Wang, Shahid M.Hussain, Gabriel P.Krestin, Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MR
imaging, Eur. Radil. 2001, 11: 2319-2331
[27] Lee Josephson, Jerome Lewis, Paula Jacobs, The effects of iron oxide on proton relaxivity, Magnetic Resonance Imaging, 1988, 6:647-653
[28] David Portet, Benoit Denizot, Elmar Rump, Nonpolymeric coatings of iron oxide colloids for biological use as magnetic resonance imaging contrast agents. Journal of Colloid and Interface Science, 2001, 238:37-42
[29] 陈龙华.磁共振成像对比剂增强理论与治疗.北京:人民卫生出版社.1995.1-113
[30] 徐亮,郭启勇.超顺磁性氧化铁的研究现状及其在肝增强磁共振成像的临床应用及前景.国外医学临床放射学分册.2000.1: 31-36
[31] 陈星荣, 沈天真, 段新祥, 等, 全身CT和MRI 上海: 上海医科大学出版社.第1版.1993.73-80
[32] 徐国财, 马家举, 邢宏龙.纳米粒子的分散及其有机复合材料的复合技术.中国科学基金.2001.2: 109-112
[33] 冯拉俊, 刘毅辉, 雷阿利.纳米颗粒团聚的控制.微纳电子技术.2003.7/8: 536-539
[34] Chaumout D, Craievich A, Zarzycki A, Effect of ultrasound on the formation of ZrO2 sols and wet gels.Journal of Non-Crystalline Solids.1992.41:147-148
[35] Emma M.Coe, Lawrence H. Bown, Alexander Speer, et al., The recharacterization of a Polysaccharide iron complex (Niferex). Joural of Inoganic Biochemistry.1995.58: 269-278
[36] 王世敏,许祖勋,傅晶.纳米材料制备技术.化学工业出版社.第1版.2002
[37] 宫杰,李海波,华中,等.松辽学刊.1994.(4)23-26
[38] Z.L.Liu, Y.J.Liu, K.L.Yao, et al, Synthesis and magnetic properties of Fe3O4 nanoparticles, J. Mater. Synth. Process. 2002, 10:83-87
[39] Bmberkoddky, VFMedvedev, et al., Magnetic Fluids-Engineering Application. Oxford University Press. 1993
[40] 蒋秉植, 杨健美, 磁流体的稳定性解析. 润滑与密封, 1995, 3: 61-65
[41] Jeckel E, Rumbach R, Uber die adsorption von hochmolekularen stoffen aus der losung. Z.Elektochem. 1951, 55: 612-618
[42] Brant D.A, Burton B.A. The configurational statistics of the pullulan and some related glucans. ACS. Symp. Ser. (Solution Properties of Polysaccharides), 1981, 150: 81-99
[43] M.Y.Gao, X.G. Peng and J.C.Shen, Polymer langmuir-blogdett film of organic-inorganic composite microgel. Thin Solid Films, 1994, 248:148-151
[44] Ros P.R, Freeny P.C, Harms S.E, et al., Hepatic MR imaging with fermoxides: A multicenter clinical trial of the safety and efficacy in the detection of focal hepatic lesions. Radiology, 1995, 196(8):481-488
[45] Seneterre E, Taourel P, Bouvier Y., et al., Detection of hepatic metastases: Ferumoxides enhanced MR imaging versus unenhanced MR imaging and CT during arterial portopragraphy. Radiology, 1996, 200(9): 785-792
[2] Junu Chatterjee, Yousef Haik, Ching-Jen Chen. Polythylene magnetic nanoparticle: a new magnetic material for biomedical applications. JMMM. 2002.246: 382-391
[3] R.S.Molday and L.L.Molday Separation of cells labeled with immunonspecific iron dextran microspheres using high magnetic chromatography. FEBS. 1984.170(2): 232-237
[4] N.Cem Balci, Mustafa Sirvanci, Cihan Duran, et al., Hepatic adenomatosis MRI demonstration with the use of superparamagnetic iron oxide. Journal of Clinical Imaging 2002, 26: 35-38
[5] Maire-France Bellin.Catherine Beigelman.Sophie Precetti-Morel. Iron oxide-enhanced MR lymphography: initial experience.European Journal of Radiology. 2000.34: 257-264
[6] 董聿生,梁峰,余向阳等.新型磁性葡聚糖亲和吸附剂的制备及其在尿激酶纯化中的应用 色谱 2000.19(1):21-24
[7] Cavicchi R E, Silsbee R H. First steps towards tailoring fine and ultrafine iron particles using micromulsions. Phys. Rev. Lett. .1984.52(5): 1453-1457
[8] M Arturo Lopez-Quintela, Jose Rivas. Chemical reaction in microemulsions: a powerful method to obtain ultrafine particles. Langmuir, 1999, 154(4): 447-453
[9] Ball P, Garwin L. Matrix-mediated synthesis of nanocrystalline r-Fe2O3: a new optically transparent magnetic material. Nature, 1992, 355: 761-771
[10] 张立德,牟季美.纳米材料和纳米结构.第2版.北京:科学出版社,2001
[11] 李国栋.金属磁性功能材料进展.金属功能材料.1996.3(6):202-204
[12] 林培豪,曾中明.磁性材料进展.物理.2000.29(6):323-332
[13] 沈良,江国华.磁性纳米功能材料研究进展.杭州师范学院学报(自然科学版).2001.18(5):40-44
[14] 都有为,徐明祥,吴坚等.镍超微颗粒的磁性.物理学报.1992, 41(1): 149-154
[15] Lin C H, Shen Z W, Wang M L. et al., Hydrothermal processing to produce magnetic particles. IEEE Trans. Magn. 1990, 26(1):15-17
[16] F.E.Spada, E.J.Mcniff Jr., S. Foner, Anomalous properties of magnetic nanopartilces. JMMM. 1999, 196:591-594
[17] Y. Jin, C.L.Dennis, S.A.Majetich, Nanoscale characterization of magnetic nanoparticles. Nanostructured Materials.1999.12: 763-768
[18] 王晨 胡军 罗伟等 磁性液体的研究进展. 金属功能材料.2003.10(4):35-38
[19] 高善民,孙树声,刘兆明.纳米材料的应用前景展望.化学世界2000, 11: 613-616
[20] 许海燕,孔桦,杨子彬.纳米材料及其在生物医学工程中的应用. 国外医学生物医学工程分册.1998.21(5):262-266
[21] Ole Diettrich, Kevin Mills, Andrew W.Johnson, et al., Application of magnetic chromatography to the isolation of lysosomes from fibroblasts of patients with lysosomal storage disorders. FEBS Letters.1998.441:369-372
[22] 沈其丰.核磁共振碳谱.第1版.北京:北京大学出版社.1988. 1-3
[23] Jeff W.M. Bulte, Marcel de Cuyper, Daryl Despres, et al., Preparation, relaxometry, and biokinetcs of PEGylated magnetoliposomes as MR contrast agent. JMMM, 2000, 194: 204-209
[24] V.Rousseau, D.Pouliquen, F.Darcel, et al., NMR investigation of experimental chemical induced brain tumors in rats, potential of a superparamagnetic contrast agent(MD3) to improve diagnosis. Magnetic Resonance Materials in Biology, Physics and Medicine.1998.6:13-21
[25] D.Pouliguen, R.Perdrisot, A.Ermias, et al., Superparamagnetic iron oxide nanoparticls as a liver MRI contrast agent: contribution of microencapsulation to improved biodistribution.Magnetic Resonance Imaging.1989.7: 619-627
[26] Yi-Xiang J.Wang, Shahid M.Hussain, Gabriel P.Krestin, Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MR
imaging, Eur. Radil. 2001, 11: 2319-2331
[27] Lee Josephson, Jerome Lewis, Paula Jacobs, The effects of iron oxide on proton relaxivity, Magnetic Resonance Imaging, 1988, 6:647-653
[28] David Portet, Benoit Denizot, Elmar Rump, Nonpolymeric coatings of iron oxide colloids for biological use as magnetic resonance imaging contrast agents. Journal of Colloid and Interface Science, 2001, 238:37-42
[29] 陈龙华.磁共振成像对比剂增强理论与治疗.北京:人民卫生出版社.1995.1-113
[30] 徐亮,郭启勇.超顺磁性氧化铁的研究现状及其在肝增强磁共振成像的临床应用及前景.国外医学临床放射学分册.2000.1: 31-36
[31] 陈星荣, 沈天真, 段新祥, 等, 全身CT和MRI 上海: 上海医科大学出版社.第1版.1993.73-80
[32] 徐国财, 马家举, 邢宏龙.纳米粒子的分散及其有机复合材料的复合技术.中国科学基金.2001.2: 109-112
[33] 冯拉俊, 刘毅辉, 雷阿利.纳米颗粒团聚的控制.微纳电子技术.2003.7/8: 536-539
[34] Chaumout D, Craievich A, Zarzycki A, Effect of ultrasound on the formation of ZrO2 sols and wet gels.Journal of Non-Crystalline Solids.1992.41:147-148
[35] Emma M.Coe, Lawrence H. Bown, Alexander Speer, et al., The recharacterization of a Polysaccharide iron complex (Niferex). Joural of Inoganic Biochemistry.1995.58: 269-278
[36] 王世敏,许祖勋,傅晶.纳米材料制备技术.化学工业出版社.第1版.2002
[37] 宫杰,李海波,华中,等.松辽学刊.1994.(4)23-26
[38] Z.L.Liu, Y.J.Liu, K.L.Yao, et al, Synthesis and magnetic properties of Fe3O4 nanoparticles, J. Mater. Synth. Process. 2002, 10:83-87
[39] Bmberkoddky, VFMedvedev, et al., Magnetic Fluids-Engineering Application. Oxford University Press. 1993
[40] 蒋秉植, 杨健美, 磁流体的稳定性解析. 润滑与密封, 1995, 3: 61-65
[41] Jeckel E, Rumbach R, Uber die adsorption von hochmolekularen stoffen aus der losung. Z.Elektochem. 1951, 55: 612-618
[42] Brant D.A, Burton B.A. The configurational statistics of the pullulan and some related glucans. ACS. Symp. Ser. (Solution Properties of Polysaccharides), 1981, 150: 81-99
[43] M.Y.Gao, X.G. Peng and J.C.Shen, Polymer langmuir-blogdett film of organic-inorganic composite microgel. Thin Solid Films, 1994, 248:148-151
[44] Ros P.R, Freeny P.C, Harms S.E, et al., Hepatic MR imaging with fermoxides: A multicenter clinical trial of the safety and efficacy in the detection of focal hepatic lesions. Radiology, 1995, 196(8):481-488
[45] Seneterre E, Taourel P, Bouvier Y., et al., Detection of hepatic metastases: Ferumoxides enhanced MR imaging versus unenhanced MR imaging and CT during arterial portopragraphy. Radiology, 1996, 200(9): 785-792
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