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Investigation of nanoparticle-cell interactions for development of next generation of biocompatible MRI contrast agents
Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
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: urn:nbn:se:liu:diva-152347ISBN: 9789176851906 (print)OAI: oai:DiVA.org:liu-152347DiVA, id: diva2:1259351
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
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
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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
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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
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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
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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.

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

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