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  • 1.
    Abrikossova, Natalia
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Investigation of nanoparticle-cell interactions for development of next generation of biocompatible MRI contrast agents2018Doctoral 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.

    List of papers
    1. Effects of gadolinium oxide nanoparticles on the oxidative burst from human neutrophil granulocytes
    Open this publication in new window or tab >>Effects of gadolinium oxide nanoparticles on the oxidative burst from human neutrophil granulocytes
    Show others...
    2012 (English)In: Nanotechnology, ISSN 0957-4484, E-ISSN 1361-6528, Vol. 23, no 27, p. 275101-Article in journal (Refereed) Published
    Abstract [en]

    We have previously shown that gadolinium oxide (Gd2O3) nanoparticles are promising candidates to be used as contrast agents in magnetic resonance (MR) imaging applications. In this study, these nanoparticles were investigated in a cellular system, as possible probes for visualization and targeting intended for bioimaging applications. We evaluated the impact of the presence of Gd2O3 nanoparticles on the production of reactive oxygen species (ROS) from human neutrophils, by means of luminol-dependent chemiluminescence. Three sets of Gd2O3 nanoparticles were studied, i.e. as synthesized, dialyzed and both PEG-functionalized and dialyzed Gd2O3 nanoparticles. In addition, neutrophil morphology was evaluated by fluorescent staining of the actin cytoskeleton and fluorescence microscopy. We show that surface modification of these nanoparticles with polyethylene glycol (PEG) is essential in order to increase their biocompatibility. We observed that the as synthesized nanoparticles markedly decreased the ROS production from neutrophils challenged with prey (opsonized yeast particles) compared to controls without nanoparticles. After functionalization and dialysis, more moderate inhibitory effects were observed at a corresponding concentration of gadolinium. At lower gadolinium concentration the response was similar to that of the control cells. We suggest that the diethylene glycol (DEG) present in the as synthesized nanoparticle preparation is responsible for the inhibitory effects on the neutrophil oxidative burst. Indeed, in the present study we also show that even a low concentration of DEG, 0.3%, severely inhibits neutrophil function. In summary, the low cellular response upon PEG-functionalized Gd2O3 nanoparticle exposure indicates that these nanoparticles are promising candidates for MR-imaging purposes.

    Place, publisher, year, edition, pages
    Institute of Physics, 2012
    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:liu:diva-79667 (URN)10.1088/0957-4484/23/27/275101 (DOI)000305802000001 ()
    Available from: 2012-08-14 Created: 2012-08-13 Last updated: 2018-11-12
    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
    Show others...
    2010 (English)In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 26, no 8, p. 5753-5762Article 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: 2018-10-29Bibliographically approved
    3. Gd2O3 nanoparticles in hematopoietic cells for MRI contrast enhancement
    Open this publication in new window or tab >>Gd2O3 nanoparticles in hematopoietic cells for MRI contrast enhancement
    Show others...
    2011 (English)In: International journal of nano medicine, ISSN 1178-2013, Vol. 6, p. 3233-3240Article in journal (Refereed) Published
    Abstract [en]

    As the utility of magnetic resonance imaging (MRI) broadens, the importance of having specific and efficient contrast agents increases and in recent time there has been a huge development in the fields of molecular imaging and intracellular markers. Previous studies have shown that gadolinium oxide (Gd2O3) nanoparticles generate higher relaxivity than currently available Gd chelates: In addition, the Gd2O3 nanoparticles have promising properties for MRI cell tracking. The aim of the present work was to study cell labeling with Gd2O3 nanoparticles in hematopoietic cells and to improve techniques for monitoring hematopoietic stem cell migration by MRI. Particle uptake was studied in two cell lines: the hematopoietic progenitor cell line Ba/F3 and the monocytic cell line THP-1. Cells were incubated with Gd2O3 nanoparticles and it was investigated whether the transfection agent protamine sulfate increased the particle uptake. Treated cells were examined by electron microscopy and MRI, and analyzed for particle content by inductively coupled plasma sector field mass spectrometry. Results showed that particles were intracellular, however, sparsely in Ba/F3. The relaxation times were shortened with increasing particle concentration. Relaxivities, r1 and r2 at 1.5 T and 21°C, for Gd2O3 nanoparticles in different cell samples were 3.6–5.3 s-1 mM-1 and 9.6–17.2 s-1 mM-1, respectively. Protamine sulfate treatment increased the uptake in both Ba/F3 cells and THP-1 cells. However, the increased uptake did not increase the relaxation rate for THP-1 as for Ba/F3, probably due to aggregation and/or saturation effects. Viability of treated cells was not significantly decreased and thus, it was concluded that the use of Gd2O3 nanoparticles is suitable for this type of cell labeling by means of detecting and monitoring hematopoietic cells. In conclusion, Gd2O3 nanoparticles are a promising material to achieve positive intracellular MRI contrast; however, further particle development needs to be performed.

    Place, publisher, year, edition, pages
    Manchester, UK: Dove Medical Press Ltd, 2011
    Keywords
    gadolinium oxide, magnetic resonance imaging, contrast agent, cell labeling, Ba/F3 cells, THP-1 cells
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-72275 (URN)10.2147/IJN.S23940 (DOI)000298164300001 ()
    Note

    funding agencies|Swedish Research Council| 621-2007-3810 621-2009-5148 521-2009-3423 |VINNOVA| 2009-00194 |Center in Nanoscience and Technology at LiTH (CeNano)||

    Available from: 2011-11-24 Created: 2011-11-24 Last updated: 2018-10-29
    4. Synthesis and Characterization of Tb3+-Doped Gd2O3 Nanocrystals: A Bifunctional Material with Combined Fluorescent Labeling and MRI Contrast Agent Properties
    Open this publication in new window or tab >>Synthesis and Characterization of Tb3+-Doped Gd2O3 Nanocrystals: A Bifunctional Material with Combined Fluorescent Labeling and MRI Contrast Agent Properties
    Show others...
    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.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-12944 (URN)10.1021/jp808708m (DOI)000265529700009 ()
    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
  • 2.
    Abrikossova, Natalia
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Skoglund, Caroline
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, The Institute of Technology.
    Ahrén, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Bengtsson, Torbjorn
    University of Örebro, Sweden .
    Uvdal, Kajsa
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Effects of gadolinium oxide nanoparticles on the oxidative burst from human neutrophil granulocytes2012In: Nanotechnology, ISSN 0957-4484, E-ISSN 1361-6528, Vol. 23, no 27, p. 275101-Article in journal (Refereed)
    Abstract [en]

    We have previously shown that gadolinium oxide (Gd2O3) nanoparticles are promising candidates to be used as contrast agents in magnetic resonance (MR) imaging applications. In this study, these nanoparticles were investigated in a cellular system, as possible probes for visualization and targeting intended for bioimaging applications. We evaluated the impact of the presence of Gd2O3 nanoparticles on the production of reactive oxygen species (ROS) from human neutrophils, by means of luminol-dependent chemiluminescence. Three sets of Gd2O3 nanoparticles were studied, i.e. as synthesized, dialyzed and both PEG-functionalized and dialyzed Gd2O3 nanoparticles. In addition, neutrophil morphology was evaluated by fluorescent staining of the actin cytoskeleton and fluorescence microscopy. We show that surface modification of these nanoparticles with polyethylene glycol (PEG) is essential in order to increase their biocompatibility. We observed that the as synthesized nanoparticles markedly decreased the ROS production from neutrophils challenged with prey (opsonized yeast particles) compared to controls without nanoparticles. After functionalization and dialysis, more moderate inhibitory effects were observed at a corresponding concentration of gadolinium. At lower gadolinium concentration the response was similar to that of the control cells. We suggest that the diethylene glycol (DEG) present in the as synthesized nanoparticle preparation is responsible for the inhibitory effects on the neutrophil oxidative burst. Indeed, in the present study we also show that even a low concentration of DEG, 0.3%, severely inhibits neutrophil function. In summary, the low cellular response upon PEG-functionalized Gd2O3 nanoparticle exposure indicates that these nanoparticles are promising candidates for MR-imaging purposes.

  • 3.
    Ahrén, Maria
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, The Institute of Technology.
    Selegård, Linnéa
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, The Institute of Technology.
    Klasson, Anna
    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.
    Söderlind, Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Abrikossova, Natalia
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, The Institute of Technology.
    Skoglund, Caroline
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Bengtsson, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, The Institute of Technology.
    Engström, Maria
    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.
    Käll, Per-Olov
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Uvdal, Kajsa
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, The Institute of Technology.
    Synthesis and Characterization of PEGylated Gd2O3 Nanoparticles for MRI Contrast Enhancement2010In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 26, no 8, p. 5753-5762Article in journal (Refereed)
    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.

  • 4.
    Hedlund, Anna
    et al.
    Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Faculty of Health Sciences.
    Ahrén, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Surface Physics and Chemistry . Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, The Institute of Technology.
    Gustafsson, Håkan
    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.
    Abrikossova, Natalia
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Warntjes, Marcel
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medical and Health Sciences, Clinical Physiology. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Uvdal, Kajsa
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics . Linköping University, The Institute of Technology.
    Engström, Maria
    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.
    Detection of Gd2O3 Nanoparticles in Hematopoietic Cells for MRI Contrast EnhancementManuscript (preprint) (Other academic)
    Abstract [en]

    As the utility of magnetic resonance imaging (MRI) broadens, the importance of having specific and efficient contrast agents increases and there has been a huge development in the fields of molecular imaging and intracellular markers.

    Previous studies have shown that gadolinium oxide (Gd2O3 ) nanoparticles generate higher relaxivity than currently available Gd chelates. The Gd2O3 nanoparticles are also promising for MRI cell tracking. The aim of the present work was to study cell labeling with Gd2O3 nanoparticles and to improve techniques for monitoring hematopoietic stem cell migration by MRI.

    We studied particle uptake in two cell lines; the hematopoietic progenitor cell line Ba/F3 and the monocytic cell line THP-1. Cells were incubated with Gd2O3 nanoparticles as well as superparamagnetic iron oxide particles (SPIOs) for comparison. In addition, it was investigated whether the transfection agent protamine sulfate increased the particle uptake. Treated cells were examined by microscopic techniques, MRI and analyzed for particle content.

    Results showed that particles were intracellular, however in Ba/F3 only sparsely. The relaxation times were shortened with increasing particle concentration. Overall relaxivities, r1 and r2 for Gd2O3 nanoparticles in all cell samples measured were 5.1 ± 0.3 and 14.9 ± 0.7 (s-1mM-1) respectively. Goodness of fit was 0.97 in both cases. Protamine sulfate treatment increased the uptake in both Ba/F3 cells and THP-1 cells.

    Viability of treated cells was not significantly decreased and thus, we conclude that the use of Gd2O3 nanoparticles is suitable for this type of cell labeling by means of detecting and monitoring hematopoietic cells.

  • 5.
    Hedlund, Anna
    et al.
    Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Health Sciences.
    Ahrén, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Gustafsson, Håkan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Abrikossova, Natalia
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Warntjes, Marcel
    Linköping University, Department of Medical and Health Sciences, Clinical Physiology. Linköping University, Faculty of Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Jönsson, Jan-Ivar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical and Physiological Chemistry.
    Uvdal, Kajsa
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Engström, Maria
    Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Health Sciences.
    Gd2O3 nanoparticles in hematopoietic cells for MRI contrast enhancement2011In: International journal of nano medicine, ISSN 1178-2013, Vol. 6, p. 3233-3240Article in journal (Refereed)
    Abstract [en]

    As the utility of magnetic resonance imaging (MRI) broadens, the importance of having specific and efficient contrast agents increases and in recent time there has been a huge development in the fields of molecular imaging and intracellular markers. Previous studies have shown that gadolinium oxide (Gd2O3) nanoparticles generate higher relaxivity than currently available Gd chelates: In addition, the Gd2O3 nanoparticles have promising properties for MRI cell tracking. The aim of the present work was to study cell labeling with Gd2O3 nanoparticles in hematopoietic cells and to improve techniques for monitoring hematopoietic stem cell migration by MRI. Particle uptake was studied in two cell lines: the hematopoietic progenitor cell line Ba/F3 and the monocytic cell line THP-1. Cells were incubated with Gd2O3 nanoparticles and it was investigated whether the transfection agent protamine sulfate increased the particle uptake. Treated cells were examined by electron microscopy and MRI, and analyzed for particle content by inductively coupled plasma sector field mass spectrometry. Results showed that particles were intracellular, however, sparsely in Ba/F3. The relaxation times were shortened with increasing particle concentration. Relaxivities, r1 and r2 at 1.5 T and 21°C, for Gd2O3 nanoparticles in different cell samples were 3.6–5.3 s-1 mM-1 and 9.6–17.2 s-1 mM-1, respectively. Protamine sulfate treatment increased the uptake in both Ba/F3 cells and THP-1 cells. However, the increased uptake did not increase the relaxation rate for THP-1 as for Ba/F3, probably due to aggregation and/or saturation effects. Viability of treated cells was not significantly decreased and thus, it was concluded that the use of Gd2O3 nanoparticles is suitable for this type of cell labeling by means of detecting and monitoring hematopoietic cells. In conclusion, Gd2O3 nanoparticles are a promising material to achieve positive intracellular MRI contrast; however, further particle development needs to be performed.

  • 6.
    Larsson, Emanuel
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, The Institute of Technology. Elettra Sincrotrone Trieste, Italy; University of Trieste, Italy.
    Dullin, Christian
    Institute of Diagnostic and Interventional Radiology, University Hospital Goettingen, Germany.
    Abrikossova, Natalia
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Brommesson, Caroline
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Mikac, Urša
    Jožef Stefan Institute, Ljubljana, Slovenia.
    Garrovo, Chiara
    Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy.
    Accardo, Agostino
    Department of Engineering and Architecture, University of Trieste, Italy.
    Tromba, Giuliana
    SYRMEP Beamline, Sincrotrone Trieste S.C.p.A, Italy.
    Serša, Igor
    Jožef Stefan Institute, Ljubljana, Slovenia.
    Uvdal, Kajsa
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Optimization of the loading efficacy for dual-modal CT/MRI macrophage tracking in lungs of an asthma mouse model2015Manuscript (preprint) (Other academic)
    Abstract [en]

    We present novel cell uptake methodologies related to the usage of MRI/CT contrast agents for the purpose of performing dual-modal cell tracking with macrophages in both MRI and CT. Two different techniques, namely Synchrotron X-rays microtomography and Micro Magnetic Resonance Imaging were used to investigate the contrast  enhancement, as an effect of the MRI/CT contrast agent cell uptake of mouse alveolar macrophages. Macrophages loaded with the  commercial contrast agent Micropaque® CT, containing barium sulphate (BaSO4) immersed in Sorbitol, showed a much higher contrast enhancement in CT, than an MRI/CT contrast agent based on Gadolinium nanoparticles (GdNPs). The CT contrast of GdNPs (at 5 mM of Gd) could be increased, by immersing the GdNPs in Sorbitol, while still maintaining a positive T1-contrast in MRI. The idea of co-loading macrophages with both BaSO4 and GdNP inside the same cells  presented a valid "trade off" between the optimal contrast in CT vs. MRI etc. It was concluded that while optimizing the cell uptake of contrast agent for cell tracking in MRI/CT, it is important to make a "trade off" between the following 3 parameters, 1) optimal contrast in CT, 2) optimal contrast in MRI and 3) metabolic cell activity, depending on the given application. These cell optimization ideas may be of importance to every field aiming to image an inflammatory disease, based on the utilization of contrast agent loaded macrophages.

  • 7.
    Larsson, Emanuel
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, The Institute of Technology. Elettra Sincrotrone Trieste, Italy; University of Trieste, Italy.
    Dullin, Christian
    Institute of Diagnostic and Interventional Radiology, University Hospital Goettingen, Germany.
    Abrikossova, Natalia
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Mikac, Urša
    Jožef Stefan Institute, Ljubljana, Slovenia.
    Brommesson, Caroline
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Accardo, Agostino
    Department of Engineering and Architecture, University of Trieste, Italy.
    Tromba, Giuliana
    SYRMEP Beamline, Sincrotrone Trieste S.C.p.A, Italy.
    Uvdal, Kajsa
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Serša, Igor
    Jožef Stefan Institute, Ljubljana, Slovenia.
    Dual-modal CT and MRI functional and anatomical imaging using barium sulphate and gadolinium nanoparticle loaded macrophages in a preclinical asthma mouse model2015Manuscript (preprint) (Other academic)
    Abstract [en]

    Objectives In this study we investigated the potentials of dual-modal CT-MRI macrophage tracking, by a intratracheal instillation of a mixture of either gadolinium nanoparticles or barium sulphate loaded alveolar macrophages into mice of an allergic airway inflammation (asthma) model and their respective healthy control, imaged with Synchrotron X-rays microtomography (SR μCT) and Micro Magnetic Resonance Imaging (μMRI).

    Materials and Methods The mice were scanned ex vivo using SRμCT at 22 keV and with a 9.4 Tesla μMRI scanner. The CT and MRI data sets were registered and fused together, followed by quantitative and statistical analysis.

    Results The asthmatic sample injected with contrast agent loaded macrophages showed high absorbing spots inside the soft-tissue regions of the lung for the CT data set, as well as higher contrast for the soft-tissue in the MRI data set. Furthermore, the correlation analysis showed a perfect negative correlation between the soft tissue mean grey value in CT and the soft tissue mean grey value in MRI.

    Conclusion The dual-modal CT-MRI cell tracking of intratracheally administered macrophages (loaded with contrast agent) in an asthmatic mouse helps to extract synergistic information about the migration  behaviour of macrophages, where clusters of cells were detected in CT, while as a general increase of the soft-tissue contrast could be observed in MRI, due to a homogeneous cell distribution.

  • 8.
    Petoral, Rodrigo M
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Söderlind, Fredrik
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Klasson, Anna
    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.
    Suska, Anke
    Linköping University, Department of Physics, Chemistry and Biology, Applied Physics. Linköping University, Faculty of Science & Engineering.
    Fortin, Marc-André
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Abrikossova, Natalia
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Selegard, Linnea
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology.
    Käll, Per-Olov
    Linköping University, Department of Physics, Chemistry and Biology, Physical Chemistry. Linköping University, The Institute of Technology.
    Engström, Maria
    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.
    Uvdal, Kajsa
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Synthesis and Characterization of Tb3+-Doped Gd2O3 Nanocrystals: A Bifunctional Material with Combined Fluorescent Labeling and MRI Contrast Agent Properties2009In: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 113, no 17, p. 6913-6920Article in journal (Refereed)
    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.

  • 9.
    Selegård, Linnéa
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Zakharov, Alexei
    MAX-lab, Lund University, Lund, Sweden.
    Skallberg, Andréas
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, The Institute of Technology.
    Abrikossova, Natalia
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Uvdal, Kajsa
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    PEEM, LEED and PES temperature study of Eu doped Gd2O3 nanoparticles and their interactions with silicon2013Manuscript (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.

  • 10.
    Uvdal, Kajsa
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics .
    Ahrén, Maria
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics .
    Selegård, Linnéa
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics .
    Abrikossova, Natalia
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics .
    Klasson, Anna
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Radiology . Linköping University, Center for Medical Image Science and Visualization, CMIV.
    Söderlind, Fredrik
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Engström, Maria
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Center for Medical Image Science and Visualization, CMIV.
    Käll, Per-Olov
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Physical Chemistry .
    Functionalized Gd2O3 Nanoparticles to Be used for MRI Contrast Enhancement2008In: AVS,2008, 2008Conference paper (Other academic)
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