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Synthesis, Surface Modification, and Characterization of Metal Oxide Nanoparticles: Nanoprobes for Signal Enhancement in Biomedical Imaging
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]

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: urn:nbn:se:liu:diva-91849ISBN: 978-91-7519-646-6 (print)OAI: oai:DiVA.org:liu-91849DiVA: diva2:619331
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
List of papers
1. ZnO Nanoparticles Functionalized with Organic Acids: An Experimental and Quantum-Chemical Study
Open this publication in new window or tab >>ZnO Nanoparticles Functionalized with Organic Acids: An Experimental and Quantum-Chemical Study
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2009 (English)In: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 113, no 40, 17332-17341 p.Article in journal (Refereed) Published
Abstract [en]

Electrochemical synthesis and physical characterization of ZnO nanoparticles functionalized with four different organic acids, three aromatic (benzoic, nicotinic, and trans-cinnamic acid) and one nonaromatic (formic acid), are reported. The functionalized nanoparticles have been characterized by X-ray powder diffraction, transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, UV−vis, and photoluminescence spectroscopy. The adsorption of the organic acids at ZnO nanoparticles was further analyzed and interpreted using quantum-chemical density-functional theory computations. Successful functionalization of the nanoparticles was confirmed experimentally by the measured splitting of the carboxylic group stretching vibrations as well as by the N(1s) and C(1s) peaks from XPS. From a comparison between computed and experimental IR spectra, a bridging mode adsorption geometry was inferred. PL spectra exhibited a remarkably stronger near band edge emission for nanoparticles functionalized with formic acid as compared to the larger aromatic acids. From the quantum-chemical computations, this was interpreted to be due to the absence of aromatic adsorbate or surface states in the band gap of ZnO, caused by the formation of a complete monolayer of HCOOH. In the UV−vis spectra, strong charge-transfer transitions were observed.

Keyword
nanoparticles, ZnO, organic acids, adsorption, synthesis, XPS, UV-vis, quantum chemical calculations
National Category
Physical Chemistry
Identifiers
urn:nbn:se:liu:diva-50783 (URN)10.1021/jp905481v (DOI)
Available from: 2009-10-14 Created: 2009-10-14 Last updated: 2017-12-12
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. Biotinylation of ZnO Nanoparticles and Thin Films: A Two-Step Surface Functionalization Study
Open this publication in new window or tab >>Biotinylation of ZnO Nanoparticles and Thin Films: A Two-Step Surface Functionalization Study
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2010 (English)In: ACS APPLIED MATERIALS and INTERFACES, ISSN 1944-8244, Vol. 2, no 7, 2128-2135 p.Article in journal (Refereed) Published
Abstract [en]

This study reports ZnO nanoparticles and thin film surface modification using a two-step functionalization strategy. A small silane molecule was used to build up a stabilizing layer and for conjugation of biotin (vitamin B7), as a specific tag. Biotin was chosen because it is a well-studied bioactive molecule with high affinity for avidin. ZnO nanoparticles were synthesized by electrochemical deposition under oxidizing condition, and ZnO films were prepared by plasma-enhanced metal organic chemical vapor deposition. Both ZnO nanoparticles and ZnO thin films were surface modified by forming a (3-mercaptopropyl)trimethoxysilane (MPTS) layer followed by attachment of a biotin derivate. lodoacetyl-PEG2-biotin molecule was coupled to the thiol unit in MPTS through a substitution reaction. Powder X-ray diffraction, transmission electron microscopy, X-ray photoemission electron microscopy, atomic force microscopy. X-ray photoelectron spectroscopy, and near-edge X-ray absorption fine structure spectroscopy were used to investigate the as-synthesized and functionalized ZnO materials. The measurements showed highly crystalline materials in both cases with a ZnO nanoparticle diameter of about 5 nm and a grain size of about 45 nm for the as-grown ZnO thin films. The surface modification process resulted in coupling of silanes and biotin to both the ZnO nanoparticles and ZnO thin films. The two-step functionalization strategy has a high potential for specific targeting in bioimaging probes and for recognition studies in biosensing applications.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 1155 16TH ST, NW, WASHINGTON, DC 20036 USA, 2010
Keyword
ZnO nanoparticles, thin films XRD, TEM, XPS, NEXAFS, biotin, PEEM
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-58542 (URN)10.1021/am100374z (DOI)000280367000049 ()
Available from: 2010-08-13 Created: 2010-08-13 Last updated: 2015-05-29
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. 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
6. PEEM, LEED and PES temperature study of Eu doped Gd2O3 nanoparticles and their interactions with silicon
Open this publication in new window or tab >>PEEM, LEED and PES temperature study of Eu doped Gd2O3 nanoparticles and their interactions with silicon
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2013 (English)Manuscript (preprint) (Other academic)
Abstract [en]

We report the formation of silicate and silicide by annealing of a SiOx surface, with low coverage of Eu doped Gd2O3 nanoparticles. Interestingly, the annealing temperature required for removal of native oxide from the Si substrate decreases with as much as 200 degrees in presence of the nanoparticles. XPEEM, LEEM and MEM are used to monitor the silicide/silicate formation and SiOx removal. Fragmentation of the nanoparticles is observed, and the SiOx layer is gradually removed. Eu is migrating to clean Si areas during the annealing process, while Gd is found in areas where oxide is still present. This annealing process is clearly facilitated in the presence of rare-earth based nanoparticles, where nanoparticles are suggested to function as reaction sites. Reduction of the annealing temperature of SiOx substrates is also observed in presence of pure Eu3+ and Gd3+ ions, but to lesser extent. The significant reduction of the annealing temperature of SiO by several hundred degrees, in presence of Eu doped Gd2O3 nanoparticles, is remarkable. This type of material may find applications both within optoelectronics and processing microelectronic industry.

Keyword
PEEM, LEED, PES, rare-earth, silicon, annealing
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-91848 (URN)
Available from: 2013-05-03 Created: 2013-05-03 Last updated: 2015-05-29Bibliographically approved

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