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Cerium Oxide Nanoparticles and Gadolinium Integration: Synthesis, Characterization and Biomedical Applications
Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.ORCID iD: 0000-0002-1192-1492
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A challenging task, in the area of magnetic resonance imaging is to develop contrast enhancers with built-in antioxidant properties. Oxidative stress is considered to be involved in the onset and progression of several serious conditions such as Alzheimer’s and Parkinson’s disease, and the possibility to use cerium-contained nanoparticles to modulate such inflammatory response has gained a lot of interest lately. The rare earth element gadolinium is, due to its seven unpaired f-electrons and high symmetry of the electronic state, a powerful element for contrast enhancement in magnetic resonance imaging. Chelates based on gadolinium are the most commonly used contrast agents worldwide. When introducing external contrast agents there is always a risk that it may trigger inflammatory responses, why there is an urgent need for new, tailor-made contrast agents.

Small sized cerium oxide nanoparticles have electronic structures that allows coexistence of oxidation states 3+ and 4+ of cerium, which correlates to applicable redox reactions in biomedicine. Such cerium oxide nanoparticles have recently shown to exhibit antioxidant properties both in vitro and in vivo, via the mechanisms involving enzyme mimicking activity.

This PhD project is a comprehensive investigation of cerium oxide nanoparticles as scaffold materials for gadolinium integration. Gadolinium is well adopted into the crystal structure of cerium oxide, enabling the combination of diagnostic and therapeutic properties into a single nanoparticle. The main focus of this thesis project is to design cerium oxide nanoparticles with gadolinium integration. A stepwise approach was employed as follows: 1) synthesis with controlled integration of gadolinium, 2) material characterization by means of composition crystal structure, size, and size distribution and 3) surface modification for stabilization. The obtained nanoparticles exhibit remarkable antioxidant capability in vitro and in vivo. They deliver strongly enhanced contrast per gadolinium in magnetic resonance imaging, compared to commercially available contrast agents.

A soft shell of dextran is introduced to encapsulate the cerium oxide nanoparticles with integrated gadolinium, which protects and stabilizes the hard core and to increases their biocompatibility. The dextran-coating is clearly shown to reduce formation of a protein corona and it improves the dispersibility of the nanoparticles in cell media. Functionalization strategies are currently being studied to endow these nanoparticles with specific tags for targeting purposes. This will enable guidance of the nanoparticles to a specific tissue, for high local magnetic resonance contrast complemented with properties for on-site reduced inflammation.

In conclusion, our cerium oxide nanoparticles with integrated gadolinium, exhibit combined therapeutic and diagnostic, i.e. theragnostic capabilities. This type of nanomaterial is highly promising for applications in the field of biomedical imaging.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2019. , p. 48
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1997
National Category
Materials Chemistry
Identifiers
URN: urn:nbn:se:liu:diva-159949DOI: 10.3384/diss.diva-159949ISBN: 9789176850299 (print)OAI: oai:DiVA.org:liu-159949DiVA, id: diva2:1346953
Public defence
2019-09-27, Planck, F Building, Campus Valla, Linköping, 10:15 (English)
Opponent
Supervisors
Available from: 2019-08-29 Created: 2019-08-29 Last updated: 2019-08-29Bibliographically approved
List of papers
1. Cerium oxide nanoparticles with antioxidant capabilities and gadolinium integration for MRI contrast enhancement
Open this publication in new window or tab >>Cerium oxide nanoparticles with antioxidant capabilities and gadolinium integration for MRI contrast enhancement
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 6999Article in journal (Refereed) Published
Abstract [en]

The chelating gadolinium-complex is routinely used as magnetic resonance imaging (MRI) -contrast enhancer. However, several safety issues have recently been reported by FDA and PRAC. There is an urgent need for the next generation of safer MRI-contrast enhancers, with improved local contrast and targeting capabilities. Cerium oxide nanoparticles (CeNPs) are designed with fractions of up to 50% gadolinium to utilize the superior MRI-contrast properties of gadolinium. CeNPs are well-tolerated in vivo and have redox properties making them suitable for biomedical applications, for example scavenging purposes on the tissue-and cellular level and during tumor treatment to reduce in vivo inflammatory processes. Our near edge X-ray absorption fine structure (NEXAFS) studies show that implementation of gadolinium changes the initial co-existence of oxidation states Ce3+ and Ce4+ of cerium, thereby affecting the scavenging properties of the nanoparticles. Based on ab initio electronic structure calculations, we describe the most prominent spectral features for the respective oxidation states. The as-prepared gadolinium-implemented CeNPs are 3-5 nm in size, have r(1)-relaxivities between 7-13 mM(-1) s(-1) and show clear antioxidative properties, all of which means they are promising theranostic agents for use in future biomedical applications.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Other Physics Topics
Identifiers
urn:nbn:se:liu:diva-147910 (URN)10.1038/s41598-018-25390-z (DOI)000431293100003 ()29725117 (PubMedID)2-s2.0-85046679522 (Scopus ID)
Note

Funding Agencies|Swedish Research Council [621-2013-5357]; Swedish Government Strategic Research Area in Materials Science on Functional Materials at Linkoping University (Faculty Grant SFO-Mat-LiU) [2009-00971]; Knut and Alice Wallenberg Foundation [2012.0083 CTS 15:507]; Centre in Nano Science and Nano technology at LiTH (CeNano) at Linkoping University; CoTXS; Ministry of Education and Science of the Russian Federation [14.Y26.31.0005, K2-2017-080, 211]

Available from: 2018-05-23 Created: 2018-05-23 Last updated: 2019-08-29Bibliographically approved

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