Projects and Grants per year
Grants and Contracts Details
Description
Nanomaterial technological development has been underway for decades. Only in the past
decade has serious attention been paid to potential unwanted effects. Many nanomaterials do
not readily dissolve or disintegrate in biological and environmental milieu. As a result, they
persist for months to years where they are sequestered (in mammals, mostly in mononuclear
phagocyte system organs such as the liver, spleen, and bone marrow), often associated with
inflammatory/oxidative stress responses, including granuloma. These unwanted effects have
been seen with nanoceria (nanoscale cerium dioxide). On the other hand, nanoceria has been
shown to be an effective anti-inflammatory/antioxidant in numerous acellular, cell, and whole
animal models of inflammation/oxidative stress. Nanoceria’s pro- and antioxidant effects result
from its auto-catalytic redox behavior (Ce(III) oxidation to Ce(IV); Ce(IV) reduction to Ce(III)).
Specific aim 1 will determine if nanoceria can produce inflammatory/pro-oxidant effects in the
absence of elevated inflammation/oxidative stress and anti-inflammatory/antioxidant effects
when inflammation/oxidative stress is elevated, and determine the lowest observed adverse and
lowest observed beneficial doses. Several nanoceria will be studied. Initially we will focus on the
5 and 30 nm ceria that we have extensively studied, to understand their behavior in the
presence of elevated oxidative stress/inflammation. We will obtain from Sudipta Seal et al or
prepare the ~ 8 nm ceria they are investigating and compare it to the 5 nm ceria for
physicochemical similarities/differences, and determine its ability to produce the adverse effects
we have seen with the 5 nm ceria. If the 5 and 8 nm ceria are not significantly different we will
continue this project with the 5, but not 8, nm ceria. Due to the very low oral and pulmonary
absorption of nanomaterials, nanoceria will be delivered intravenously to establish sufficient
levels in multiple organs to study its biodistribution, persistence, biotransformation, and effects.
Preliminary findings indicate that nanoceria undergoes some bioprocessing in mammals over
months, to a more stable form. This appears to occur via dissolution and formation of very small
nanoceria particles, which have a greater surface Ce(III) enrichment; therefore expected to have
enhanced anti-inflammatory/antioxidant properties. This biotransformation suggests enhanced
benefit over time associated with nanoceria’s persistence and bioprocessing. Specific aim 2 will
identify factors that contribute to nanoceria dissolution and precipitation and mediate its
bioprocessing and precipitation in the liver. The proposed studies will test the hypothesis that
the same nanoceria can both increase and decrease inflammation/oxidative stress depending
on the initial level of stress, identify nanoceria doses that maximize its efficacy relative to its
unwanted effects, and provide insight into its biotransformation that may enable safer by design
nanoceria for use as a therapeutic agent with prolonged anti-inflammatory/antioxidant activity.
Status | Finished |
---|---|
Effective start/end date | 6/1/15 → 5/31/20 |
Funding
- National Institute of General Medical Sciences
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Projects
- 1 Finished
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Reconciling Nanoceria's Jekyll and Hyde Reputation Toward Safer Nanotherapy
Yokel, R., Butterfield, D. A., Stromberg, A., Unrine, J., Graham, U. & Grulke, E.
National Institute of General Medical Sciences
6/1/15 → 5/31/21
Project: Research project