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Metal Oxide Nanoparticles for Contrast Enhancement in Magnetic Resonance Imaging: Synthesis, Functionalization and Characterization
Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, The Institute of Technology.
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: urn:nbn:se:liu:diva-98693DOI: 10.3384/diss.diva-98693ISBN: 978-91-7519-522-3 (print)OAI: oai:DiVA.org:liu-98693DiVA: diva2:655367
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
List of papers
1. Positive MRI Enhancement in THP-1 Cells with Gd2O3 Nanoparticles
Open this publication in new window or tab >>Positive MRI Enhancement in THP-1 Cells with Gd2O3 Nanoparticles
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2008 (English)In: Contrast Media and Molecular Imaging, ISSN 1555-4309, Vol. 3, no 3, 106-111 p.Article in journal (Refereed) Published
Abstract [en]

There is a demand for more efficient and tissue-specific MRI contrast agents and recent developments involve the design of substances useful as molecular markers and magnetic tracers. In this study, nanoparticles of gadolinium oxide (Gd2O3) have been investigated for cell labeling and capacity to generate a positive contrast. THP-1, a monocytic cell line that is phagocytic, was used and results were compared with relaxivity of particles in cell culture medium (RPMI 1640). The results showed that Gd2O3-labeled cells have shorter T1 and T2 relaxation times compared with untreated cells. A prominent difference in signal intensity was observed, indicating that Gd2O3 nanoparticles can be used as a positive contrast agent for cell labeling. The r1 for cell samples was 4.1 and 3.6 s-1 mm-1 for cell culture medium. The r2 was 17.4 and 12.9 s-1 mm-1, respectively. For r1, there was no significant difference in relaxivity between particles in cells compared to particles in cell culture medium, (pr1 = 0.36), but r2 was significantly different for the two different series (pr2 = 0.02). Viability results indicate that THP-1 cells endure treatment with Gd2O3 nanoparticles for an extended period of time and it is therefore concluded that results in this study are based on viable cells.

Keyword
gadolinium oxide, nanoparticles, contrast agent, THP-1 cells, magnetic resonance imaging
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-12945 (URN)10.1002/cmmi.236 (DOI)000257982000002 ()
Available from: 2008-02-21 Created: 2008-02-21 Last updated: 2017-09-22Bibliographically approved
2. Synthesis and Characterization of PEGylated Gd2O3 Nanoparticles for MRI Contrast Enhancement
Open this publication in new window or tab >>Synthesis and Characterization of PEGylated Gd2O3 Nanoparticles for MRI Contrast Enhancement
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2010 (English)In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 26, no 8, 5753-5762 p.Article in journal (Refereed) Published
Abstract [en]

Recently, much attention has been given to the development of biofunctionalized nanoparticles with magnetic properties for novel biomedical imaging. Guided, smart, targeting nanoparticulate magnetic resonance imaging (MRI) contrast agents inducing high MRI signal will be valuable tools for future tissue specific imaging and investigation of molecular and cellular events. In this study, we report a new design of functionalized ultrasmall rare earth based nanoparticles to be used as a positive contrast agent in MRI. The relaxivity is compared to commercially available Gd based chelates. The synthesis, PEGylation, and dialysis of small (3−5 nm) gadolinium oxide (DEG-Gd2O3) nanoparticles are presented. The chemical and physical properties of the nanomaterial were investigated with Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, transmission electron microscopy, and dynamic light scattering. Neutrophil activation after exposure to this nanomaterial was studied by means of fluorescence microscopy. The proton relaxation times as a function of dialysis time and functionalization were measured at 1.5 T. A capping procedure introducing stabilizing properties was designed and verified, and the dialysis effects were evaluated. A higher proton relaxivity was obtained for as-synthesized diethylene glycol (DEG)-Gd2O3 nanoparticles compared to commercial Gd-DTPA. A slight decrease of the relaxivity for as-synthesized DEG-Gd2O3 nanoparticles as a function of dialysis time was observed. The results for functionalized nanoparticles showed a considerable relaxivity increase for particles dialyzed extensively with r1 and r2 values approximately 4 times the corresponding values for Gd-DTPA. The microscopy study showed that PEGylated nanoparticles do not activate neutrophils in contrast to uncapped Gd2O3. Finally, the nanoparticles are equipped with Rhodamine to show that our PEGylated nanoparticles are available for further coupling chemistry, and thus prepared for targeting purposes. The long term goal is to design a powerful, directed contrast agent for MRI examinations with specific targeting possibilities and with properties inducing local contrast, that is, an extremely high MR signal at the cellular and molecular level.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2010
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-54946 (URN)10.1021/la903566y (DOI)000276562300061 ()
Available from: 2010-04-23 Created: 2010-04-23 Last updated: 2017-12-12Bibliographically approved
3. Magnetic and Electron Spin Relaxation Properties of (GdxY1-x)2O3 (0 ≤ x ≤ 1) Nanoparticles Synthesized by the Combustion Method. Increased Electron Spin Relaxation Times with Increasing Yttrium Content
Open this publication in new window or tab >>Magnetic and Electron Spin Relaxation Properties of (GdxY1-x)2O3 (0 ≤ x ≤ 1) Nanoparticles Synthesized by the Combustion Method. Increased Electron Spin Relaxation Times with Increasing Yttrium Content
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2011 (English)In: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 115, no 13, 5469-5477 p.Article in journal (Refereed) Published
Abstract [en]

The performance of a magnetic resonance imaging contrast agent (CA) depends on several factors, including the relaxation times of the unpaired electrons in the CA. The electron spin relaxation time may be a key factor for the performance of new CAs, such as nanosized Gd2O3 particles. The aim of this work is, therefore, to study changes in the magnetic susceptibility and the electron spin relaxation time of paramagnetic Gd2O3 nanoparticles diluted with increasing amounts of diamagnetic Y2O3. Nanoparticles of (GdxY1-x)2O3 (0 e x e 1) were prepared by the combustion method and thoroughly characterized (by X-ray di.raction, transmission electron microscopy, thermogravimetry coupled with mass spectroscopy, photoelectron spectroscopy, Fourier transform infrared spectroscopy, and magnetic susceptibility measurements). Changes in the electron spin relaxation time were estimated by observations of the signal line width in electron paramagnetic resonance spectroscopy, and it was found that the line width was dependent on the concentration of yttrium, indicating that diamagnetic Y2O3 may increase the electron spin relaxation time of Gd2O3 nanoparticles.

Place, publisher, year, edition, pages
United States: American Chemical Society, 2011
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-67439 (URN)10.1021/jp111368t (DOI)000288885900036 ()
Available from: 2011-04-13 Created: 2011-04-12 Last updated: 2017-12-11Bibliographically approved
4. A simple polyol-free synthesis route to Gd2O3 nanoparticles for MRI applications: an experimental and theoretical study
Open this publication in new window or tab >>A simple polyol-free synthesis route to Gd2O3 nanoparticles for MRI applications: an experimental and theoretical study
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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
Keyword
Gadolinium oxide, Synthesis, Relaxivity, XPS, IR, Toxicity
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-81505 (URN)10.1007/s11051-012-1006-2 (DOI)000307273400028 ()
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: 2017-12-07
5. Highly Water-Dispersible Surface-Modified Gd2O3 Nanoparticles for Potential Dual-Modal Bioimaging
Open this publication in new window or tab >>Highly Water-Dispersible Surface-Modified Gd2O3 Nanoparticles for Potential Dual-Modal Bioimaging
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2013 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 19, no 38, 12658-12667 p.Article in journal (Refereed) Published
Abstract [en]

Water-dispersible and luminescent gadolinium oxide (GO) nanoparticles (NPs) were designed and synthesized for potential dual-modal biological imaging. They were obtained by capping gadolinium oxide nanoparticles with a fluorescent glycol-based conjugated carboxylate (HL). The obtained nanoparticles (GO-L) show long-term colloidal stability and intense blue fluorescence. In addition, L can sensitize the luminescence of europium(III) through the so-called antenna effect. Thus, to extend the spectral ranges of emission, europium was introduced into L-modified gadolinium oxide nanoparticles. The obtained Eu-III-doped particles (Eu:GO-L) can provide visible red emission, which is more intensive than that without L capping. The average diameter of the monodisperse modified oxide cores is about 4nm. The average hydrodynamic diameter of the L-modified nanoparticles was estimated to be about 13nm. The nanoparticles show effective longitudinal water proton relaxivity. The relaxivity values obtained for GO-L and Eu:GO-L were r(1)=6.4 and 6.3s(-1)mM(-1) with r(2)/r(1) ratios close to unity at 1.4T. Longitudinal proton relaxivities of these nanoparticles are higher than those of positive contrast agents based on gadolinium complexes such as Gd-DOTA, which are commonly used for clinical magnetic resonance imaging. Moreover, these particles are suitable for cellular imaging and show good biocompatibility.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2013
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-98690 (URN)10.1002/chem.201301687 (DOI)000324316300018 ()
Available from: 2013-10-11 Created: 2013-10-11 Last updated: 2017-12-06Bibliographically approved
6. Bifunctional gadolinium decorated ZnO nanocrystals integrating both enhanced MR signal and bright fluorescence
Open this publication in new window or tab >>Bifunctional gadolinium decorated ZnO nanocrystals integrating both enhanced MR signal and bright fluorescence
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2013 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Gadolinium decorated ZnO nanoparticles simultaneously possess both fluorescent and MR enhancement properties. These ZnO nanoparticles are crystalline and shielded by an amorphous gadolinium acetate matrix. Interestingly, the Gd-acetate decoration enhances the fluorescence emission of the ZnO nanoparticles. The quantum yield does increase for samples with high Gd/Zn relative ratios and these samples do also show a higher colloidal stability.

In addition, these nanoparticles show an enhanced relaxivity value per Gd atom (r119.9mM1s-1) compared to results earlier reported both on Gd alloyed ZnO nanoparticles and pure Gd2O3 nanoparticles. This improvement is considered to be due to the close proximity of Gd atoms and surrounding water molecules. A comprehensive study of the quantum yield and the relaxivity, as a function of composition, enable us to identify the ultimate design/composition of gadolinium decorated ZnO nanoparticles for optimum fluorescence and MR enhancement properties.

National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-91847 (URN)
Available from: 2013-05-03 Created: 2013-05-03 Last updated: 2015-05-29Bibliographically approved
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