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A simple polyol-free synthesis route to Gd2O3 nanoparticles for MRI applications: an experimental and theoretical study
Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
Linköping University, Department of Physics, Chemistry and Biology, Nanostructured Materials. Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Computational Physics. Linköping University, The Institute of Technology.
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2012 (English)In: Journal of nanoparticle research, ISSN 1388-0764, E-ISSN 1572-896X, Vol. 14, no 8Article in journal (Refereed) Published
Abstract [en]

Chelated gadolinium ions, e. g., GdDTPA, are today used clinically as contrast agents for magnetic resonance imaging (MRI). An attractive alternative contrast agent is composed of gadolinium oxide nanoparticles as they have shown to provide enhanced contrast and, in principle, more straightforward molecular capping possibilities. In this study, we report a new, simple, and polyol-free way of synthesizing 4-5-nm-sized Gd2O3 nanoparticles at room temperature, with high stability and water solubility. The nanoparticles induce high-proton relaxivity compared to Gd-DTPA showing r(1) and r(2) values almost as high as those for free Gd3+ ions in water. The Gd2O3 nanoparticles are capped with acetate and carbonate groups, as shown with infrared spectroscopy, near-edge X-ray absorption spectroscopy, X-ray photoelectron spectroscopy and combined thermogravimetric and mass spectroscopy analysis. Interpretation of infrared spectroscopy data is corroborated by extensive quantum chemical calculations. This nanomaterial is easily prepared and has promising properties to function as a core in a future contrast agent for MRI.

Place, publisher, year, edition, pages
Springer Verlag (Germany) , 2012. Vol. 14, no 8
Keyword [en]
Gadolinium oxide, Synthesis, Relaxivity, XPS, IR, Toxicity
National Category
Engineering and Technology
Identifiers
URN: urn:nbn:se:liu:diva-81505DOI: 10.1007/s11051-012-1006-2ISI: 000307273400028OAI: oai:DiVA.org:liu-81505DiVA: diva2:553099
Note

Funding Agencies|VINNOVA|2008-03011|Centre in Nanoscience and Technology at LiTH (CeNano)||Swedish research council|621-2010-5014|SERC (Swedish e-Science Research Center)||

Available from: 2012-09-18 Created: 2012-09-18 Last updated: 2015-05-29
In thesis
1. Synthesis, Surface Modification, and Characterization of Metal Oxide Nanoparticles: Nanoprobes for Signal Enhancement in Biomedical Imaging
Open this publication in new window or tab >>Synthesis, Surface Modification, and Characterization of Metal Oxide Nanoparticles: Nanoprobes for Signal Enhancement in Biomedical Imaging
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis we investigate crystalline metal oxide nanoparticles of our own design to obtain nanoprobes for signal enhancement and bioimaging purposes. We report fabrication, surface modification and characterization of nanoparticles based on zinc (Zn), and rare earths (i.e. gadolinium (Gd) and europium (Eu)) singly and in combination. Our ZnO nanoparticles show high potential as fluorescent probes and Gd2O3 nanoparticles are promising as nanoprobes for MR signal enhancement. A combined Zn, Gd material is investigated as a potential dual probe. Interestingly, this nanoprobe shows, compared to the pure oxides, both increased fluorescent quantum yield and do induce improved relaxivity and by that enhanced MR signal. Nanoparticles composed of Eu doped Gd2O3 are also investigated in terms of their ability to interact with silicon surfaces. The presence of nanoparticles shows a catalytic effect on the annealing procedure of SiOx.

Surface modification of Gd and Zn based nanoparticles is performed, in a first step to improve stabilization of the nanoparticle core. Both carboxylic acids (paper I) and a thiol terminated silane (paper II and III) are used for this purpose. In a second step, a polyethylene glycol (PEG) is used for surface modification, to increase the biocompatibility of the nanoparticles. The Mal PEG NHS is chemically linked to thiol terminated silane groups via a maleimide coupling (Paper II). The presence of free NHS functional groups is intended to enable further linking of specific molecules for targeting purposes. The fluorescent dye rhodamine was, as a proof of concept, linked via the NHS functional group to the PEGylated Gd2O3 nanoparticles (Paper II). In Paper III, an alternative linking strategy is investigated, using iodized PEG2-Biotin for coupling via the iodide unit to the thiol terminated silane on ZnO nanoparticles. The resulting surface modified nanoparticles are investigated by means of coordination chemistry and coupling efficiency using X-ray photoelectron spectroscopy, near edge X-ray absorption fine structure  spectroscopy and infrared spectroscopy.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. 58 p.
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1510
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-91849 (URN)978-91-7519-646-6 (print) (ISBN)
Public defence
2013-05-24, Planck, Fysikhuset, Campus Valla, Linköpings universitet, Linköping, 10:15 (Swedish)
Opponent
Supervisors
Available from: 2013-05-03 Created: 2013-05-03 Last updated: 2015-06-03Bibliographically approved
2. Metal Oxide Nanoparticles for Contrast Enhancement in Magnetic Resonance Imaging: Synthesis, Functionalization and Characterization
Open this publication in new window or tab >>Metal Oxide Nanoparticles for Contrast Enhancement in Magnetic Resonance Imaging: Synthesis, Functionalization and Characterization
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis work focuses on the design and production of nanoparticle based contrast agents for signal enhancement in magnetic resonance imaging (MRI). Three different synthesis routes are explored, primarily to produce crystalline gadolinium oxide (Gd2O3) nanoparticles, and surface modification is done to obtain stable, dispersible, biocompatible probes inducing high proton relaxivities.

In Paper I and II we utilized the polyol synthesis method and nanoparticle purification was performed with dialysis. Active surface functionalization was achieved by an innermost layer of 3-mercaptopropyl trimetoxy silanes (MPTS) and an outer layer of bifunctional PEG. Surface capping was shown to greatly affect the water proton relaxation to a degree which is strongly dependent on the purification time. PEGylation also induced stabilizing effects and the ability to provide the nanoparticles with luminescent properties was proven by linking the fluorescent dye Rhodamine to the bifunctional PEG.

In Paper III the magnetic behavior of yttrium (Y) alloyed Gd2O3 nanoparticles was investigated as a function of Y concentration. This was done by performing magnetic measurements and by studying the signal line width in electron paramagnetic resonance spectroscopy for Gd2O3, Y2O3 and a series of (GdxY1-x)2O3 samples produced using the combustion synthesis. The results verified that the signal line width is dependent on the percent of yttrium dilution. This is considered as an indication of that yttrium dilution changes the electron spin relaxation time in Gd2O3.

Paper IV and V present a novel precipitation synthesis method for Gd2O3 nanoparticles. Acetate molecular groups were found to coordinate the nanoparticle surface increasing the water dispersability. The Gd2O3 nanoparticles induce a twice as high relaxivity per gadolinium atom, as compared to the commercially available contrast agent Magnevist. Incorporation of luminescent europium (Eu3+) ions into the Gd2O3 nanoparticles in combination with surface modification with a fluorescent branched carboxyl terminated TEG, produced dual probes with tunable luminescence, maintained relaxivity and thus a bright contrast in MRI.

In Paper VI, a new approach to accomplish a dual probe was investigated. Luminescent ZnO nanoparticles decorated with Gd ions bound in an organic matrix were evaluated for MR signal enhancement and ability to function as fluorescent probes. Interestingly, these nanoprobes did show an enhanced capability to both strengthen the MR signal and increase the fluorescent quantum yield, as compared to the pure oxides.

In Paper VII we investigate sub 5 nm crystalline manganese based nanoparticles produced by the precipitation synthesis used for Gd2O3 nanoparticles. Manganese oxide was chosen as another candidate for MRI contrast enhancement as it is expected to have a straight forward surface coupling chemistry. Characterization of the crystal structure and chemical composition indicated nanoparticles with a MnO core and presence of manganese species of higher valences at the nanoparticle surface. The MnO nanomaterial showed a superparamagnetic behavior and less capability to increase the MR signal as compared to Gd2O3.

Characterization of the nanoparticle crystal structure and size is, throughout the work, performed by means of transmission electron microscopy, X-ray diffraction and dynamic light scattering. The chemical composition is studied with X-ray photoelectron spectroscopy, infrared spectroscopy and near edge X-ray absorption fine structure spectroscopy and the fluorescence characteristics are evaluated with fluorescence spectroscopy. In addition, theoretical models and calculated IR spectroscopy and near edge X-ray absorption fine structure spectroscopy data have been used for evaluation of experimental results.

To conclude, the aim of this work is the design, production and characterization of ultrasmall rare earth based nanoparticles for signal enhancement in biomedical imaging. Surface modification clearly increases the colloidal stability and biocompatibility of the nanoparticles. Compared to the agents in clinical use today, these nanoprobes have a higher capability to enhance the MR-signal, and they will in the near future be equipped with tags for specific targeting.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. 82 p.
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1541
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-98693 (URN)10.3384/diss.diva-98693 (DOI)978-91-7519-522-3 (print) (ISBN)
Public defence
2013-11-15, Brillouin, Fysikhuset, Campus Valla, Linköpings universitet, Linköping, 10:15 (Swedish)
Opponent
Supervisors
Available from: 2013-10-11 Created: 2013-10-11 Last updated: 2015-06-03Bibliographically approved

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