亲水性磁性纳米复合粒子的制备和普通铼的标记实验
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摘要
本文采用不同的制备方法制得亲水性羧基化磁性纳米粒子,并进行表征分析,然后选用性能最优的磁性纳米粒子进行后续生物分子的接枝改性,为下一步的普通铼标记奠定基础。具体内容如下：
首先,分别采用水热法制备簇状Fe3O4二次磁性纳米粒子和高温分解法制备单分散Fe3O4磁性纳米粒子,两类反应都选用聚丙烯酸做稳定剂和表面改性剂,但是选用不同的铁源,水热法用乙酰丙酮铁Fe(acac)3、高温分解法用无水FeCl3,并通过TEM、FTIR、TG、XRD、VSM等分析手段表征分析优选出粒径(100nm左右和10nm以内)、磁含量(76%和71%)和饱和磁化强度(Ms:39 emu/g和36.8 emu/g)等性能最优的高温分解法制得的粒子作为后续改性实验用。本文并对羧基化Fe304粒子的制备机理进行详细分析,阐述水热法中粒径生成趋势和高温分解法中粒子成核、长大过程的机理。
其次,在选用的羧基化Fe304粒子表面接枝生物分子(赖氨酸、牛血清蛋白、叶酸),借助EDC/NHS偶合进行酰胺化反应,然后通过TEM、FTIR、TG、UV、VSM等分析手段确认生物分子是否成功地接枝在粒子表面,其中叶酸改性的粒子,粒径20nm以内,饱和磁化强度为29emu/g,最后推导出羧基化粒子氨基化、酰胺化反应过程,以及赖氨酸偶合反应的详细反应。
最后,开展叶酸改性磁性纳米粒子的普通铼的标记实验,将制得的FA@MNPs和NaReO4混合在一起,在前驱体fac-[Re(CO)3(H2O)3]+生成的同时螯合叶酸,磁吸法除杂后用XPS表征最后得到的黑色磁性物质,机理分析三羰基铼的生成过程,并确认最后FA@MNPs顺利螯合fac-[Re(CO)3(H2O)3]+,为实现放射性铼188Re的标记实验以及放疗应用奠定基础。
The hydrophilic carboxylated magnetic nanoparticles were prepared via different soft chemical methods and the better one with greatest properties was chosen by characterized for later functionalized with biomaterials and then applied in the radiolabeling with no-radioactive rhenium. The details were described as follows:
Firstly, the secondary cluster magnetic nanoparticles were prepared by hydrothermal synthesis and the monodisperse magnetic nanoparticles were prepared via thermal decomposition synthesis which both used poly(acrylic acid) as the stabilizer and surface modifier while chosing different iron source. The synthesized products were characterized by TEM, FTIR, TG, XRD, VSM and so on. The results showed that better nanopartics were prepared the thermal decomposition synthesis with average size of less than 10 nm, the magnetic content of 71% and the saturation magnetization of 36.8 emu/g which would be used for later functionalion. Then the formation mechanism of carboxylated Fe3O4 magnetic nanopartics synthesis was analysed in detail including the NP's growing trend in the hydrothermal synthesis and NP's nucleation and growth in thermal decomposition synthesis.
Secondly, biomaterials (lysine, BSA and folate) were grafting on to the surface of carboxylated magnetic nanoparticls via the water-soluble EDC/NHS mediated coupling reactions. The synthesized products were characterized by TEM, FTIR, TG, UV, VSM to ensure the biomaterials had been successfully coated. The results showed that folate grafted on to the magnetic nanoparticles with the average diameter of 20 nm and saturation magnetization of 29 emu/g. Subsequently, the formation mechanism of carboxylated magnetic nanoparticles with acylation and amidation reaction was explained in detail which took the coupling with lysine as example.
Finally, the basic labeling study based on non-radioactive rhenium was carried out with mixing synthesized FA@MNPs with NaReO4. Thus fac-[Re(CO)3(H2O)3]+ was prepared and was chelated with nanoparticles at the same time and the products were purified with NdFeB magnets. The black magnetic nanoparticles were characterized by XPS to ensure the existence of rhenium element with the formation mechanism of rhenium carbonyl compound. The element researches offered the theoretical basis and experimental foundation for the follow-up successful labeling of radioactive nuclear 188Re on the magnetic nanoparticles.
首先,分别采用水热法制备簇状Fe3O4二次磁性纳米粒子和高温分解法制备单分散Fe3O4磁性纳米粒子,两类反应都选用聚丙烯酸做稳定剂和表面改性剂,但是选用不同的铁源,水热法用乙酰丙酮铁Fe(acac)3、高温分解法用无水FeCl3,并通过TEM、FTIR、TG、XRD、VSM等分析手段表征分析优选出粒径(100nm左右和10nm以内)、磁含量(76%和71%)和饱和磁化强度(Ms:39 emu/g和36.8 emu/g)等性能最优的高温分解法制得的粒子作为后续改性实验用。本文并对羧基化Fe304粒子的制备机理进行详细分析,阐述水热法中粒径生成趋势和高温分解法中粒子成核、长大过程的机理。
其次,在选用的羧基化Fe304粒子表面接枝生物分子(赖氨酸、牛血清蛋白、叶酸),借助EDC/NHS偶合进行酰胺化反应,然后通过TEM、FTIR、TG、UV、VSM等分析手段确认生物分子是否成功地接枝在粒子表面,其中叶酸改性的粒子,粒径20nm以内,饱和磁化强度为29emu/g,最后推导出羧基化粒子氨基化、酰胺化反应过程,以及赖氨酸偶合反应的详细反应。
最后,开展叶酸改性磁性纳米粒子的普通铼的标记实验,将制得的FA@MNPs和NaReO4混合在一起,在前驱体fac-[Re(CO)3(H2O)3]+生成的同时螯合叶酸,磁吸法除杂后用XPS表征最后得到的黑色磁性物质,机理分析三羰基铼的生成过程,并确认最后FA@MNPs顺利螯合fac-[Re(CO)3(H2O)3]+,为实现放射性铼188Re的标记实验以及放疗应用奠定基础。
The hydrophilic carboxylated magnetic nanoparticles were prepared via different soft chemical methods and the better one with greatest properties was chosen by characterized for later functionalized with biomaterials and then applied in the radiolabeling with no-radioactive rhenium. The details were described as follows:
Firstly, the secondary cluster magnetic nanoparticles were prepared by hydrothermal synthesis and the monodisperse magnetic nanoparticles were prepared via thermal decomposition synthesis which both used poly(acrylic acid) as the stabilizer and surface modifier while chosing different iron source. The synthesized products were characterized by TEM, FTIR, TG, XRD, VSM and so on. The results showed that better nanopartics were prepared the thermal decomposition synthesis with average size of less than 10 nm, the magnetic content of 71% and the saturation magnetization of 36.8 emu/g which would be used for later functionalion. Then the formation mechanism of carboxylated Fe3O4 magnetic nanopartics synthesis was analysed in detail including the NP's growing trend in the hydrothermal synthesis and NP's nucleation and growth in thermal decomposition synthesis.
Secondly, biomaterials (lysine, BSA and folate) were grafting on to the surface of carboxylated magnetic nanoparticls via the water-soluble EDC/NHS mediated coupling reactions. The synthesized products were characterized by TEM, FTIR, TG, UV, VSM to ensure the biomaterials had been successfully coated. The results showed that folate grafted on to the magnetic nanoparticles with the average diameter of 20 nm and saturation magnetization of 29 emu/g. Subsequently, the formation mechanism of carboxylated magnetic nanoparticles with acylation and amidation reaction was explained in detail which took the coupling with lysine as example.
Finally, the basic labeling study based on non-radioactive rhenium was carried out with mixing synthesized FA@MNPs with NaReO4. Thus fac-[Re(CO)3(H2O)3]+ was prepared and was chelated with nanoparticles at the same time and the products were purified with NdFeB magnets. The black magnetic nanoparticles were characterized by XPS to ensure the existence of rhenium element with the formation mechanism of rhenium carbonyl compound. The element researches offered the theoretical basis and experimental foundation for the follow-up successful labeling of radioactive nuclear 188Re on the magnetic nanoparticles.
引文
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[2]Christoph A, Rainer T, Eveline S, et al. Cancer therapy with drug loaded magnetic nanoparticles-magnetic drug targeting. Journal of Magnetism and Magnetic and Materials,2011,323(10):1404-1407
[3]Manuel A, Rodrigo F-P, Rcardo I M, et al. Magnetic nanoparticles for drug delivery. Nanotoday,2007,2(3):23-32
[4]Gao J H, Gu H W, Xu B. Multifunctional magnetic nanoparticles:design, synthesis, and biomedical applications. Accounts of Chemical research,2009, 42(8):1097-1107
[5]Qiang Y, Antony J J, Sharma A, et al. Iron/iron oxide core-shell nanoclusters for biomedical applications. Springer,2006,8(3-4):489-496
[6]Sophie L, Delphine F, Marc P, et al. Magnetic iron oxide nanoparticles:synthesis, stabilization, vectorization, physicochemical characterizations, and biological applications. Chem. Rev.,2008,108(6):2064-2110
[7]Gupta A K, Gupta M. Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications. Biomaterials,2005, 26(18):3995-4021
[8]Cao Q L, Han X T, Li L. Enhancement of the efficiency of magnetic targeting for drug delivery:development and evaluation of magnet system. Journal of Magnetism and Magnetic Materials,2011,323(15):1919-1924
[9]Muller C, Dumas C, Hoffmann U, et al. Organomatallic 99mTc-technetium(Ⅰ)-and Re-rhenium(Ⅰ)-filate derivatives for potential use in nuclear medicine. Journal of Organometallic Chemistry,2004(689):4712-2721
[10]Gilchrist R K, Medal R, Shorey W D. Selective inductive heating of lymph nodes. Ann. Surg.,1996,146:596-606
[11]Schwertman U, Cornell R M. Iron oxide in the laboratory:preparation and characterization. Weinheim, Cambridg:VCH,1991
[12]Morteza M, Shilpa S, Wang B, et al. Superparamagnetic iron oxide nanoparticles (SPIONs):development, surface modification and application in chemotherapy. Advanced Drug Delivery Reviews,2011,63(1-2):24-46
[13]Lu A H, Salabas E L, Schuth F. Magnetic nanoparticles:synthesis, protection, functionalization, and application. Angew. Chem. Int. Ed.,2007,46(8): 1222-1244
[14]Varanda L C, Jafelicci M, Tartaj P, et al. Structural and magnetic transformation of monodispersed iron oxide particles in a reducing atmosphere. Journal of Applied Physics,2002,92 (4):2079-2085
[15]Jason R M, Weissleder R. Multifunctional magnetic nanoparticles for targeted imaging and therapy. Advanced Drug Delivery Reviews,2008, 60(11):1241-1251
[16]Hao R, Xing R J, Xu Z C, et al. Synthsis, functionalization, and biomedical applications of multifunctional magnetic nanoparticles. Adv. Mater.,2010, 22(25):2279-2742
[17]Stuart C M, Humphery H P, Dobson J. Magnetic nanoparticles for gene and drug delivery. International Journal of Nnaomedicine,2008,3(2):169-180
[18]Veiseh O, Jonathan W G, et al. Design and fabrication of magnetic nanoparticles for targeted drug delivery and imaging. Advanced Drug Delivery Reviews, 2010,62(3):284-304
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