Cerium is a rare earth element of the lanthanide series whose oxide form has been extensively used as a catalyst in many industrial processes. Cerium oxide nanoparticles are currently being studied for use in solid oxide fuel cells and as catalysts in catalytic converters primarily based on unique properties of oxygen vacancies within the cerium oxide lattice. In addition to industrial uses, recent evidence reported in the literature suggests that ceria nanoparticles can scavenge radicals and act as potent antioxidants in cell culture models and animal studies. Cerium nanoparticles have shown lifespan extension in primary neuronal cultures as well as protection from radiation induced cell death by apoptosis. Although it is clear these nanoparticles are impacting the cell in a profound way, the molecular mechanism by which these nanoparticles act is not well understood. Our recent studies have uncovered a potential molecular mechanism for this protection.
The aims of this application focus on elucidating the biophysical properties of vacancy engineered nanoparticles that result in this antioxidant activity. We will synthesize ceria nanoparticles that vary in size and oxidation state (Cerium in +3 versus +4 states). We will test these nanoparticles for their antioxidant potential in both biochemical assays as well as cell culture based experiments. We will test these particles using a well established culture model for aging, human lung fibroblasts. Once the biophysical properties that are responsible for this antioxidant activity are uncovered, we will optimize the synthesis of ceria nanoparticles so that future studies based on these can move to animal experiments to determine the efficacy of vacancy engineered nanoparticles to treat or even prevent disease. Previous studies have shown that treatment of human and animal cells in culture with vacancy engineered ceria nanoparticles results in increased lifespan of these cells. Our preliminary data have likely uncovered the molecular mechanism behind this protection. The proposed studies have the potential to produce safe nanoparticles that can be further tested for treatment of diseases that are related to elevated oxidative damage to tissues such as cardiovascular disease, Alzheimer's disease and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG031529-03
Application #
7795856
Study Section
Special Emphasis Panel (ZRG1-BST-M (50))
Program Officer
Finkelstein, David B
Project Start
2008-03-01
Project End
2012-02-28
Budget Start
2010-03-15
Budget End
2011-02-28
Support Year
3
Fiscal Year
2010
Total Cost
$259,370
Indirect Cost
Name
University of Central Florida
Department
Biochemistry
Type
Schools of Medicine
DUNS #
150805653
City
Orlando
State
FL
Country
United States
Zip Code
32826
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Dowding, J M; Song, W; Bossy, K et al. (2014) Cerium oxide nanoparticles protect against A?-induced mitochondrial fragmentation and neuronal cell death. Cell Death Differ 21:1622-32
Dowding, Janet M; Seal, Sudipta; Self, William T (2013) Cerium oxide nanoparticles accelerate the decay of peroxynitrite (ONOO(-)). Drug Deliv Transl Res 3:375-9
Dowding, Janet M; Das, Soumen; Kumar, Amit et al. (2013) Cellular interaction and toxicity depend on physicochemical properties and surface modification of redox-active nanomaterials. ACS Nano 7:4855-68
Das, Soumen; Dowding, Janet M; Klump, Kathryn E et al. (2013) Cerium oxide nanoparticles: applications and prospects in nanomedicine. Nanomedicine (Lond) 8:1483-508
Dowding, Janet M; Dosani, Talib; Kumar, Amit et al. (2012) Cerium oxide nanoparticles scavenge nitric oxide radical (ýýNO). Chem Commun (Camb) 48:4896-8
Singh, Virendra; Singh, Sanjay; Das, Soumen et al. (2012) A facile synthesis of PLGA encapsulated cerium oxide nanoparticles: release kinetics and biological activity. Nanoscale 4:2597-605
Das, Soumen; Singh, Sanjay; Dowding, Janet M et al. (2012) The induction of angiogenesis by cerium oxide nanoparticles through the modulation of oxygen in intracellular environments. Biomaterials 33:7746-55
Singh, Sanjay; Dosani, Talib; Karakoti, Ajay S et al. (2011) A phosphate-dependent shift in redox state of cerium oxide nanoparticles and its effects on catalytic properties. Biomaterials 32:6745-53
Pirmohamed, Talib; Dowding, Janet M; Singh, Sanjay et al. (2010) Nanoceria exhibit redox state-dependent catalase mimetic activity. Chem Commun (Camb) 46:2736-8

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