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Synthesis and Characterization of PEGylated Gd2O3 Nanoparticles for MRI Contrast Enhancement
Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär ytfysik och nanovetenskap. Linköpings universitet, Tekniska högskolan.
Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär ytfysik och nanovetenskap. Linköpings universitet, Tekniska högskolan.
Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutionen för medicin och hälsa, Medicinsk radiologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
Vise andre og tillknytning
2010 (engelsk)Inngår i: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 26, nr 8, s. 5753-5762Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
American Chemical Society (ACS), 2010. Vol. 26, nr 8, s. 5753-5762
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-54946DOI: 10.1021/la903566yISI: 000276562300061OAI: oai:DiVA.org:liu-54946DiVA, id: diva2:312023
Tilgjengelig fra: 2010-04-23 Laget: 2010-04-23 Sist oppdatert: 2018-10-29bibliografisk kontrollert
Inngår i avhandling
1. Synthesis, Surface Modification, and Characterization of Metal Oxide Nanoparticles: Nanoprobes for Signal Enhancement in Biomedical Imaging
Åpne denne publikasjonen i ny fane eller vindu >>Synthesis, Surface Modification, and Characterization of Metal Oxide Nanoparticles: Nanoprobes for Signal Enhancement in Biomedical Imaging
2013 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2013. s. 58
Serie
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1510
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-91849 (URN)978-91-7519-646-6 (ISBN)
Disputas
2013-05-24, Planck, Fysikhuset, Campus Valla, Linköpings universitet, Linköping, 10:15 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2013-05-03 Laget: 2013-05-03 Sist oppdatert: 2015-06-03bibliografisk kontrollert
2. Metal Oxide Nanoparticles for Contrast Enhancement in Magnetic Resonance Imaging: Synthesis, Functionalization and Characterization
Åpne denne publikasjonen i ny fane eller vindu >>Metal Oxide Nanoparticles for Contrast Enhancement in Magnetic Resonance Imaging: Synthesis, Functionalization and Characterization
2013 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2013. s. 82
Serie
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1541
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-98693 (URN)10.3384/diss.diva-98693 (DOI)978-91-7519-522-3 (ISBN)
Disputas
2013-11-15, Brillouin, Fysikhuset, Campus Valla, Linköpings universitet, Linköping, 10:15 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2013-10-11 Laget: 2013-10-11 Sist oppdatert: 2015-06-03bibliografisk kontrollert
3. Investigation of nanoparticle-cell interactions for development of next generation of biocompatible MRI contrast agents
Åpne denne publikasjonen i ny fane eller vindu >>Investigation of nanoparticle-cell interactions for development of next generation of biocompatible MRI contrast agents
2018 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Progress in synthesis technologies and advances in fundamental understanding of materials with low dimensionality has led to the birth of a new scientific field, nanoscience, and to strong expectations of multiple applications of nanomaterials. The physical properties of small particles are unique, bridging the gap between atoms and molecules, on one side, and bulk materials on the other side. The work presented in this thesis investigates the potential of using magnetic nanoparticles as the next generation of contrast agents for biomedical imaging. The focus is on gadolinium-based nanoparticles and cellular activity including the uptake, morphology and production of reactive oxygen species.

Gd ion complexes, like Gd chelates, are used today in the clinic, world-wide. However, there is a need for novel agents, with improved contrast capabilities and increased biocompatibility. One avenue in their design is based on crystalline nanoparticles. It allows to reduce the total number of Gd ions needed for an examination. This can be done by nanotechnology, which allows one to improve and fine tune the physico- chemical properties on the nanomaterial in use, and to increase the number of Gd atoms at a specific site that interact with protons and thereby locally increase the signal. In the present work, synthesis, purification and surface modification of crystalline Gd2O3-based nanoparticles have been performed. The nanoparticles are selected on the basis of their physical properties, that is they show enhanced magnetic properties and therefore may be of high potential interest for applications as contrast agents.

The main synthesis method of Gd2O3 nanoparticles in this work was the modified “polyol” route, followed by purification of as-synthesized DEG-Gd2O3 nanoparticles suspensions. In most cases the purification step involved dialysis of the nanoparticle samples. In this thesis, organosilane were chosen as an exchange agent for further functionalization. Moreover, several paths have been explored for modification of the nanoparticles, including Tb3+ doping and capping with sorbitol.

Biocompatibility of the newly designed nanoparticles is a prerequisite for their use in medical applications. Its evaluation is a complex process involving a wide range of biological phenomena. A promising path adopted in this work is to study of nanoparticle interactions with isolated blood cells. In this way one could screen nanomaterial prior to animal studies.

The primary cell type considered in the thesis are polymorphonuclear neutrophils (PMN) which represent a type of the cells of human blood belonging to the granulocyte family of leukocytes. PMNs act as the first defense of the immune system against invading pathogens, which makes them valuable for studies of biocompatibility of newly synthesized nanoparticles. In addition, an immortalized murine alveolar macrophage cell line (MH-S), THP-1 cell line, and Ba/F3 murine bone marrow-derived cell line were considered to investigate the optimization of the cell uptake and to examine the potential of new intracellular contrast agent for magnetic resonance imaging.

In paper I, the nanoparticles were investigated in a cellular system, as potential probes for visualization and targeting intended for bioimaging applications. The production of reactive oxygen species (ROS) by means of luminol-dependent chemiluminescence from human neutrophils was studied in presence of Gd2O3 nanoparticles. In paper II, a new design of functionalized ultra-small rare earth-based nanoparticles was reported. The synthesis was done using polyol method followed by PEGylation, and dialysis. Supersmall gadolinium oxide (DEG-Gd2O3) nanoparticles, in the range of 3-5 nm were obtained and carefully characterized. Neutrophil activation after exposure to this nanomaterial was studied by means of fluorescence microscopy. In paper III, cell labeling with Gd2O3 nanoparticles in hematopoietic cells was monitored by magnetic resonance imaging (MRI). In paper IV, ultra-small gadolinium oxide nanoparticles doped with terbium ions were synthesized as a potentially bifunctional material with both fluorescent and magnetic contrast agent properties. Paramagnetic behavior was studied. MRI contrast enhancement was received, and the luminescent/ fluorescent property of the particles was attributable to the Tb3+ ion located on the crystal lattice of the Gd2O3 host. Fluorescent labeling of living cells was obtained. In manuscript V, neutrophil granulocytes were investigated with rapid cell signaling communicative processes in time frame of minutes, and their response to cerium-oxide based nanoparticles were monitored using capacitive sensors based on Lab-on-a-chip technology. This showed the potential of label free method used to measure oxidative stress of neutrophil granulocytes. In manuscript VI, investigations of cell-(DEGGd2O3) nanoparticle interactions were carried out. Plain (DEG-Gd2O3) nanoparticles, (DEG-Gd2O3) nanoparticles in presence of sorbitol and (DEG-Gd2O3) nanoparticles capped with sorbitol were studied. Relaxation studies and measurements of the reactive oxygen species production by neutrophils were based on chemiluminescence. Cell morphology was evaluated as a parameter of the nanoparticle induced inflammatory response by means of the fluorescence microscopy.

The thesis demonstrates high potential of novel Gd2O3-based nanoparticles for development of the next generation contrast agents, that is to find biocompatible compounds with high relaxivity that can be detected at lower doses, and in the future enable targeting to provide great local contrast.

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2018. s. 78
Serie
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1961
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-152347 (URN)9789176851906 (ISBN)
Disputas
2018-11-21, Planck, Fysikhuset, Campus Valla, Linköping, 10:15 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2018-10-29 Laget: 2018-10-29 Sist oppdatert: 2018-10-29bibliografisk kontrollert

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