目前市面上用於核磁共振(MRI)的顯影劑,主要是以釓為主的螯合物(GD-EDTA,GD-DOTA)。因為氧化釓的製備相對簡單,加上核磁共振的成像比釓的螯合物好。近幾年來,越來越多人研究氧化釓(Gd2O3)在核磁共振上面的應用。
此篇主要探討在2種不同的方法下,合成氧化釓金屬氧化物,以及其特性的分析.第一種方式是水熱法(hydrothermal method),合成出來的氧化釓粒徑大小在100奈米左右。由於此方式必須經由鍛燒來得到氧化釓,加上氧化釓本身難容於水,所以我們藉由修飾氧化釓的表面,能使表面具有親水的基團(OH),進一步的分散在水中。
第二種方式是用多元醇法(Polyol method)來合成粒徑大小約在5奈米左右的氧化釓。由於表面有二乙二醇(DEG)包覆,氧化釓可以形成均勻奈米粒子且不聚集的分散在水中。其中我們也合成粒徑小於20奈米的氧化鐵(Fe3O4),將兩種金屬氧化物混和後,藉由表面修飾的方式,讓矽可以同時包覆住氧化釓跟氧化鐵奈米粒子,形成複合材料。

Commonly used contrast agents for MRI are chelate of Gd. Because chelated Gd ions are distributed or attached in organisms of body, Gd2O3 should be better than chelate of Gd for MRI image. More and more Gd2O3 research is for application to MRI in recent years.
In this research, we use two methods to synthesize Gd2O3 nanoparticles and assess their characteristics. First synthesis is based on the hydrothermal method and the calcining procedure and produced Gd2O3 with particle size of about 100nm. Because as-prepared Gd2O3 is hardly dispersed in water, we modified surface of Gd2O3 by tetraethyl orthosilicate. After the surface modification, since OH group coated on the Gd2O3 surface, the dispersion in water was improved.
Second, to prepare smaller size of Gd2O3, we used the polyol method. Because DEG (diethylene glycol) coated on Gd2O¬3 surface, we could synthesize Gd2O3 particles, which were uniform size (about 5nm) and dispersed in water. On the other hand, we prepared magnetite (Fe3O4) nanoparticles, size of which was less than 20 nm. After mixed two metal oxide (Gd2O3 and Fe3O4), silica was coated on the surface of Fe3O4 and Gd2O3 at the same time.

1. Lauffer RB, Paramagnetic metal-complexes as water proton relaxation agents for NMR Imaging-theory and design. Chem Rev, 1987, 87, 901-927.
2. Caravan P, Ellison JJ, McMury TJ, Lauffer RB. Gadolinium(III) chelates as MRI contrast agents: structure, dynamics, and applications. Chem Rev, 1999, 99, 2293-2352.
3. Damadian R. Tumor detection by nuclear magnetic resonance. Science, 1971, 171, 1151-1153.
4. Wener EJ, Datta A, Jocher CJ, Raymond KN. High relaxivity MRI contrast agents: where coordination chemistry meets medical imaging. Angew Chem Int Ed, 2008, 47, 8568-8580.
5. Caravan P. Strategies for increasing the sensitivity of gadolinium based MRI contrast agents. Chem Soc Rev, 2006, 35, 512–523.
6. Villaraza AJL, Bumb A, Brechbiel MW. Macromolecules, dendrimers, and nanomaterials in magnetic resonance imaging: the interplay between size, function, and pharmacokinetics. Chem Rev, 2010, 110, 2921–2959.
7. Aime S, Crich SG, Gianolio E, Giovenzana GB, Tei L, Terreno E. High sensitivity lanthanide(III) based probes for MR-medical imaging. Coord Chem Rev, 2006, 250, 1562–1579.
8. Kamaly N, Miller AD, Bell JD. Chemistry of tumour targeted T1 based MRI contrast agents. Curr Top Med Chem, 2010, 10, 1158–1183.
9. Gore JC, Manning HC, Quarles CC, Waddell KW, Yankeelov TE. Magnetic resonance in the era of molecular imaging of cancer. Magn Reson Imaging. 2011, 29, 587–600.
10. Glunde K, Artemov D, PenetMF, Jacobs MA, Bhujwalla ZM. Magnetic resonance spectroscopy in metabolic and molecular imaging and diagnosis of cancer. Chem Rev, 2010, 110, 3043–3059.
11. Caravan P, Cloutier NJ, Greenfield MT,McDermid SA, Dunham SU, Bulte JW, Amedio JC, Jr., Looby RJ, Supkowski RM, Horrocks WD, Jr. et al. The interaction of MS-325 with human serum albumin and its effect on proton relaxation rates. J Am Chem Soc, 2002, 124, 3152–3162.
12. Rohrer M, Bauer H, Mintorovitch J, Requardt M, Weinmann HJ. Comparison of magnetic properties of MRI contrast media solutions at different magnetic field strengths. Invest Radiol, 2005, 40, 715–724.
13. Lansman JB. Blockade of current through single calcium channels by trivalent lanthanide cations-effect of ionic radius on the rates of ion entry and exit. J Gen Physiol, 1990, 95, 679–696.
14. Biagi BA, Enyeart JJ. Gadolinium blocks low-threshold and high-threshold calcium currents in pituitary-cells. Am J Physiol, 1990, 259, C515–C520.
15. Laurent S, Elst LV, Copoix F, Muller RN. Stability of MRI paramagnetic contrast media—a proton relaxometric protocol for transmetallation assessment. Invest Radiol, 2001, 36, 115–122.
16. Greenberg SA. Zinc transmetallation and gadolinium retention after MR imaging: case report. Radiology, 2010, 257, 670–673.
17. Zhou Z, Lu ZR. Gadolinium-based contrast agents for magnetic resonance cancer imaging. Wiley Interdiscip Rev Nanomed Nanobiotechnol, 2013, 5, 1–18.
18. Dillman JR, Ellis JH, Cohan RH et al. Frequency and severity of acute allergic-like reactions to gadolinium-containing i.v. contrast media in children and adults. AJR Am J Roentgenol, 2007 189, 1533–1538.
19. Bleicher AG, Kanal E. Assessment of adverse reaction rates to a newly approved MRI contrast agent: review of 23,553 administrations of gadobenate dimeglumine. AJR Am J Roentgenol, 2008, 191, W307–W311.
20. Grobner T. Gadolinium: a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?. Nephrol Dial Transplant, 2006, 21, 1104–1108.
21. U.S. Food & Drug Administration (2007) Public health advisory: gadolinium-containing contrast agents for magnetic resonance imaging (MRI)—Omniscan, OptiMARK, Magnevist, ProHance, and MultiHance. http://www.fda.gov/Drugs/ DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm053112.htm. Accessed 28 June 2017.
22. Wang Y, Alkasab TK, Narin O et al. Incidence of nephrogenic systemic fibrosis after adoption of restrictive gadolinium-based contrast agent guidelines. Radiology, 2011, 260, 105–112.
23. Adin ME, Kleinberg L, Vaidya D et al. Hyperintense dentate nuclei on T1-weighted MRI: relation to repeat gadolinium administration. AJNR Am J Neuroradiol, 2015, 36, 1859–1865.
24. McDonald RJ, McDonald JS, Kallmes DF et al. Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology, 2015, 275, 772–782.
25. Robert P, Lehericy S, Grand S et al. T1-weighted hypersignal in the deep cerebellar nuclei after repeated administrations of gadolinium-based contrast agents in healthy rats: difference between linear and macrocyclic agents. Investig Radiol, 2015, 50, 473–480.
26. Ramalho J, Castillo M, Alobaidy M et al. High signal intensity in globus pallidus and dentate nucleus on unenhanced T1- weighted MR images: evaluation of two linear gadolinium-based contrast agents. Radiology, 2015, 276, 836–844.
27. Robert P, Violas X, Grand S et al. Linear gadolinium-based contrast agents are associated with brain gadolinium retention in healthy rats. Investig Radiol, 2016, 51, 73–82.
28. Jost G, Lenhard DC, Sieber MA. Signal increase on unenhanced T1-weighted images in the rat brain after repeated, extended doses of gadolinium-based contrast agents: comparison of linear and macrocyclic agents. Investig Radiol, 2016, 51, 83–89.
29. Kanda T, Osawa M, Oba H et al. High signal intensity in dentate nucleus on unenhanced T1-weighted MR images: association with linear versus macrocyclic gadolinium chelate administration. Radiology, 2015, 275, 803–809.
30. Cao Y, Huang DQ, Shih G et al. Signal change in the dentate nucleus on T1-weighted MR images after multiple administrations of gadopentetate dimeglumine versus gadobutrol. AJR Am J Roentgenol, 2016, 206, 414–419.
31. Weberling LD, Kieslich PJ, Kickingereder P et al. Increased signal intensity in the dentate nucleus on unenhanced T1-weighted images after gadobenate dimeglumine administration. Investig Radiol, 2015, 50, 743–748.
32. U.S. Food & Drug Administration (2015) FDA drug safety communication:FDA evaluating the risk of brain deposits with repeateduse of gadolinium-based contrast agents for magnetic resonanceimaging (MRI). http://www.fda.gov/Drugs/ DrugSafety/ucm455386.htm. Accessed 30 June 2017.
33. Sipe JC, Filippi M, Martino G, Furlan R, Rocca MA, Rovaris M, Bergami A, Zyroff J, Scotti G, Comi G, Method for intracellular magnetic labeling of human mononuclear cells using approved iron contrast agents. Magnetic Resonance Imaging, 1999, 17, 1521– 1523.
34. E. Farrell, P. Wielopolskix, P. Pavljasevic, N. Kops, H. Weinans, M.R. Bernsenx, G.J.V.M. van Osch, Cell labelling with superparamagnetic iron oxide has no effect on chondrocyte behavior. Osteoarthritis and Cartilage, 2009, 17, 961–967.
35. Y. Yoshida, S. Fukui, S. Fujimoto, F. Mishima, S. Takeda, Y. Izumi, S. Ohtani, Y. Fujitani, S. Nishijima, Ex vivo investigation of magnetically targeted drug delivery system. J Magnetism Magnetic Materials, 2007, 310, 2880–2882.
36. S. Bucak, D.A. Jones, P.E. Laibinis, T.A. Hatton, Protein separations using colloidal magnetic nanoparticles. Biotechnology Progress, 2003, 19, 477–484.
37. B.H. Jun, M.S. Noh, G.S. Kim, H.M. Kang, J.H. Kim, W.J. Chung, M.S. Kim, Y.K. Kim, M.H. Cho, D.H. Jeong, Y.S. Lee, Protein separation and identification using magnetic beads encoded with surface-enhanced Raman spectroscopy. Analytical Biochemistry, 2009, 391, 24–30.
38. M. Corti, A. Lascialfari, G.S. Marinone, A. Masotti, E. Micotti, F. Orsini, G. Ortaggi, G. Poletti, C. Innocenti, C. Sangregorio, Magnetic and relaxometric properties of polyethylenimine-coated superparamagnetic MRI contrast agents. J Magnetism Magnetic Materials, 2008, 320, 316–319.
39. T.K. Jain, J. Richey, M. Strand, D.L. Leslie-Pelecky, C.A. Flask, V. Labhasetwar, Magnetic nanoparticles with dual functional properties: drug delivery and magnetic resonance imaging. Biomaterials, 2008, 29, 4012–4021.
40. R.D. Hergt, S. Dutz, Magnetic particle hyperthermia: biophysical limitations of a visionary tumour therapy. J Magnetism Magnetic Materials, 2007, 311, 187–192.
41. A. Jordan, R. Scholz, P. Wust, H. Fa¨hling, R. Felix, Magnetic fluid hyperthermia (MFH): cancer treatment with AC magnetic field induced excitation of biocompatible superparamagnetic nanoparticles. J Magnetism Magnetic Materials, 1999, 201, 413–419.
42. Stephen ZR, Kievit FM, Zhang M. Magnetite nanoparticles for medical MR imaging. Mater. Today, 2011, 14, 330-338.
43. Gossuin Y, Gillis P, Hocq A, Vuong QL, Roch A. Magnetic resonance relaxation properties of superparamagnetic particles. Nanomed Nanobiotech, 2009, 1, 299-310.
44. Hedlund, A., et al., Gd2O3 nanoparticles in hematopoietic cells for MRI contrast enhancement. International journal of nanomedicine, 2011. 6: p. 3233.
45. Gayathri, T., N.M. Sundaram, and R.A. Kumar, Gadolinium Oxide Nanoparticles for Magnetic Resonance Imaging and Cancer Theranostics. Journal of Bionanoscience, 2015. 9(6): p. 409-423.

46. Matijević, E. and W.P. Hsu, Preparation and properties of monodispersed colloidal particles of lanthanide compounds: I. Gadolinium, europium, terbium, samarium, and cerium (III). Journal of Colloid and Interface Science, 1987. 118(2): p. 506-523.
47. Jain, A., et al., Synthesis and characterization of (3-Aminopropyl) trimethoxy-silane (APTMS) functionalized Gd2O3: Eu3+ red phosphor with enhanced quantum yield. Nanotechnology, 2015. 27(6): p. 065601.
48. Santra, S., et al., Synthesis and characterization of silica-coated iron oxide nanoparticles in microemulsion: the effect of nonionic surfactants. Langmuir, 2001. 17(10): p. 2900-2906.
49. Liu, B., et al., Preparation of core-shell SiO2/Fe3O4 nanocomposite particles via sol-gel approach. Wuji Cailiao Xuebao/Journal of Inorganic Materials, 2008. 23(1): p. 33-38.
50. Kim, M.T., Deposition behavior of hexamethydisiloxane films based on the FTIR analysis of Si–O–Si and Si–CH 3 bonds. Thin Solid Films, 1997. 311(1): p. 157-163.
51. Petoral Jr, R.M., et al., Synthesis and characterization of Tb3+-doped Gd2O3 nanocrystals: a bifunctional material with combined fluorescent labeling and MRI contrast agent properties. The Journal of Physical Chemistry C, 2009. 113(17): p. 6913-6920.
52. Bazzi, R., et al., Synthesis and properties of europium-based phosphors on the nanometer scale: Eu 2 O 3, Gd 2 O 3: Eu, and Y 2 O 3: Eu. Journal of colloid and interface science, 2004. 273(1): p. 191-197.
53. Yang, J., et al., One-step aqueous solvothermal synthesis of In2O3 nanocrystals. Crystal Growth and Design, 2007. 8(2): p. 695-699.
54. Caruntu, D., et al., Reactivity of 3d transition metal cations in diethylene glycolsolutions. Synthesis of transition metal ferrites with the structure of discrete nanoparticles complexed with long-chain carboxylate anions. Inorganic chemistry, 2002. 41(23): p. 6137-6146.
55. Riyahi-Alam, S., et al., Size reproducibility of gadolinium oxide based nanomagnetic particles for cellular magnetic resonance imaging: effects of functionalization, chemisorption and reaction conditions. Iranian journal of pharmaceutical research: IJPR, 2015. 14(1): p. 3.
56. Rani, S. and G. Varma, Superparamagnetism and metamagnetic transition in Fe 3 O 4 nanoparticles synthesized via co-precipitation method at different pH. Physica B: Condensed Matter, 2015. 472: p. 66-77.
57. Mascolo, M.C., Y. Pei, and T.A. Ring, Room temperature co-precipitation synthesis of magnetite nanoparticles in a large pH window with different bases. Materials, 2013. 6(12): p. 5549-5567.
58. Lu, Y., et al., Modifying the surface properties of superparamagnetic iron oxide nanoparticles through a sol− gel approach. Nano letters, 2002. 2(3): p. 183-186.