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Synthesis and Characterization of Tb3+-Doped Gd2O3 Nanocrystals: A Bifunctional Material with Combined Fluorescent Labeling and MRI Contrast Agent Properties
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. Linköping University, The Institute of Technology.
Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medical Imaging, Department of Radiology in Linköping.
Linköping University, Department of Physics, Chemistry and Biology, Applied Physics. Linköping University, Faculty of Science & Engineering.
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2009 (English)In: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 113, no 17, p. 6913-6920Article in journal (Refereed) Published
Abstract [en]

Ultrasmall gadolinium oxide nanoparticles doped with terbium ions were synthesized by the polyol route and characterized as a potentially bifunctional material with both fluorescent and magnetic contrast agent properties. The structural, optical, and magnetic properties of the organic-acid-capped and PEGylated Gd2O3:Tb3+ nanocrystals were studied by HR-TEM, XPS, EDX, IR, PL, and SQUID. The luminescent/fluorescent property of the particles is attributable to the Tb3+ ion located on the crystal lattice of the Gd2O3 host. The paramagnetic behavior of the particles is discussed. Pilot studies investigating the capability of the nanoparticles for fluorescent labeling of living cells and as a MRI contrast agent were also performed. Cells of two cell lines (THP-1 cells and fibroblasts) were incubated with the particles, and intracellular particle distribution was visualized by confocal microscopy. The MRI relaxivity of the PEGylated nanoparticles in water at low Gd concentration was assessed showing a higher T-1 relaxation rate compared to conventional Gd-DTPA chelates and comparable to that of undoped Gd2O3 nanoparticles.

Place, publisher, year, edition, pages
2009. Vol. 113, no 17, p. 6913-6920
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:liu:diva-12944DOI: 10.1021/jp808708mISI: 000265529700009OAI: oai:DiVA.org:liu-12944DiVA, id: diva2:17498
Note

On the day of the defence date the status of this article was Submitted

Available from: 2008-02-21 Created: 2008-02-21 Last updated: 2018-10-29Bibliographically approved
In thesis
1. MRI Contrast Enhancement using Gd2O3 Nanoparticles
Open this publication in new window or tab >>MRI Contrast Enhancement using Gd2O3 Nanoparticles
2008 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

There is an increasing interest for nanomaterials in biomedical applications and in this work, nanoparticles of gadolinium oxide (Gd2O3) have been investigated as a novel contrast agent for Magnetic Resonance Imaging (MRI). Relaxation properties have been studied in aqueous solutions as well as in cell culture medium and the nanoparticles have been explored as cell labeling agents. The fluorescent properties of the particles were used to visualize the internalization in cells and doped particles were also investigated as a multimodal agent that could work as a fluorescent marker for microscopy and as a contrast enhancer for MRI.

Results show that in aqueous solutions, there is a twofold increase in relaxivity for Gd2O3 compared to commercial agent Gd-DTPA. In cell culture medium as well as in cells, there is a clear T1 effect and a distinct increase in signal intensity in T1-mapped images. Fluorescent studies show that the Gd2O3 nanoparticles doped with 5% terbium have interesting fluorescent properties and that these particles could work as a multimodal contrast agent.

This study shows that Gd2O3 nanoparticles possess excellent relaxation properties that are retained in more biological environments. Gd2O3 particles are suitable as a T1 contrast agent, but seem also be adequate for T2 enhancement in for instance cell labeling experiments.

Place, publisher, year, edition, pages
Universitetsbibliotek, 2008. p. 116
Series
Linköping Studies in Health Sciences. Thesis, ISSN 1100-6013 ; 85
Keywords
nanoparticles, gadolinium oxide, magnetic resonance imaging, contrast agent
National Category
Clinical Science
Identifiers
urn:nbn:se:liu:diva-11041 (URN)978-91-7393-966-9 (ISBN)
Presentation
2008-03-07, Conrad, Huvudblocket, plan 11, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Supervisors
Available from: 2008-02-21 Created: 2008-02-21 Last updated: 2013-09-04
2. MRI Contrast Enhancement and Cell Labeling using Gd2O3 Nanoparticles
Open this publication in new window or tab >>MRI Contrast Enhancement and Cell Labeling using Gd2O3 Nanoparticles
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There is an increasing interest for nanomaterials in bio-medical applications and in this work, nanoparticles of gadolinium oxide (Gd2O3 ) have been investigated as a novel contrast agent for magnetic resonance imaging (MRI). Relaxation properties have been studied in aqueous solutions as well as in cell culture medium and the nanoparticles have been explored as cell labeling agents. The fluorescent properties of the particles were used to visualize the internalization in cells and doped particles were investigated as a multimodal agent that could work as a fluorescent marker for microscopy and as a contrast enhancer for MRI. Fluorescent studies show that the Gd2O3 nanoparticles doped with 5% terbium have interesting fluorescent properties and that these particles could work as such multimodal contrast agent. Relaxivity measurements show that in aqueous solutions, there is a twofold increase in relaxivity for Gd2O3 compared to commercial agent Gd-DTPA. In cell culture medium as well as in cells, there is a clear T1 effect and an increase in signal intensity in T1-mapped images. The cellular uptake of Gd2O3 nanoparticles were increased with the use of transfection agent protamine sulfate. This work shows that Gd2O3 nanoparticles possess good relaxation properties that are retained in different biological environments. Gd2O3 particles are suitable as a T1 contrast agent, but seem also be adequate for T2 enhancement in forinstance cell labeling experiments.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2011. p. 73
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1230
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-68802 (URN)978-91-7393-215-8 (ISBN)
Public defence
2011-06-08, Wrannesalen, Universitetssjukhuset, CMIV, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2011-06-07 Created: 2011-06-07 Last updated: 2013-09-05Bibliographically approved
3. Investigation of nanoparticle-cell interactions for development of next generation of biocompatible MRI contrast agents
Open this publication in new window or tab >>Investigation of nanoparticle-cell interactions for development of next generation of biocompatible MRI contrast agents
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2018. p. 78
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1961
National Category
Materials Chemistry Immunology
Identifiers
urn:nbn:se:liu:diva-152347 (URN)9789176851906 (ISBN)
Public defence
2018-11-21, Planck, Fysikhuset, Campus Valla, Linköping, 10:15 (English)
Opponent
Supervisors
Available from: 2018-10-29 Created: 2018-10-29 Last updated: 2018-10-29Bibliographically approved

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Petoral, Rodrigo MKlasson, AnnaSuska, AnkeFortin, Marc-AndréAbrikossova, NataliaKäll, Per-OlovEngström, MariaUvdal, Kajsa

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Molecular Surface Physics and Nano ScienceFaculty of Science & EngineeringDepartment of Physics, Chemistry and BiologyThe Institute of TechnologyCenter for Medical Image Science and Visualization (CMIV)RadiologyFaculty of Health SciencesDepartment of Radiology in LinköpingApplied PhysicsSensor Science and Molecular PhysicsPhysical Chemistry
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