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Shape-specific Effects of Cerium Oxide Nanoparticles (CNPs) on Macrophage Polarization

RAKSHE, VISHAL (2018) Shape-specific Effects of Cerium Oxide Nanoparticles (CNPs) on Macrophage Polarization. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Immunotherapy is gaining traction in healthcare research where immune activation is central to the therapeutic interventions. The field of immunotherapy is expected to grow at 15% annually and surpass $100 billion by 2022. The mainstay of immunotherapy revolves around monoclonal antibodies, cytokines, immune-modulators, and checkpoint inhibitors. Fast track approval of newer drugs like Keytruda® (Pembrolizumab, Merck) reveals the need and potential of such medications.
Evidence suggests that the activated macrophages by themselves are capable of identifying and alleviating viral infections. Macrophages display remarkable plasticity and change their phenotype in response to environmental cues. These changes give rise to different populations of cells with distinct functions namely M1 and M2. The goal of the current clinical trials involving lipopolysaccharide (LPS) or muramyldipeptide (MDP) or cytokines such as interferon-γ (IFN-γ) and granulocyte-macrophage colony-stimulating factor (GM-CSF) is to activate macrophages as a novel immunotherapeutic approach. However, inability of LPS to be systemically administered without causing toxicity in vivo or short duration of action of MDP and IFN-γ due to rapid clearance has limited their transition as effective clinical alternatives.
Cerium oxide NPs (CNPs) are known to mitigate oxidative stress and alter the free radical balance. Some recent studies suggest that microenvironmental factors such as free radicals can affect macrophage polarization. On the other hand, various nanoparticles (NPs) have shown to modulate
Shape-specific Effects of Cerium Oxide Nanoparticles (CNPs) on Macrophage Polarization
Vishal Prabhakar Rakshe, B. Pharm.
University of Pittsburgh, 2018
macrophage activation by virtue of their shape. However, interplay between NP shape effects and free radical modulating activity on the macrophage polarization is not known. Thus, we hypothesized that the shape specific CNPs can influence the macrophage phenotypes through their dual attributes: free radical modulating ability and their shapes with various aspect ratios.
We used THP-1 human monocyte cell line as an in vitro model. THP-1 monocytes were pre-differentiated to M1 and M2 macrophage phenotypes using appropriate stimuli. Measurement of reactive oxygen and nitrogen species provided an early indication that CNP shape and duration of treatment influenced the inflammatory status of the macrophages. Quantification of mRNA levels of selected M1 and M2 markers revealed shape-dependent effect of CNPs on driving macrophage polarization towards a particular phenotype. Isotropic shape such as Sphere CNPs did not show tendency to drive phenotypic changes. However, anisotropic shapes with different aspect ratios such as Cube (1:1) and Rod (21:1) CNPs showcased a high proclivity to induce an inflammatory M1 phenotype. The ability of Cube and Rod CNPs to increase reactive oxygen and nitrogen species and simultaneously drive M1 phenotype evident from gene expression profiles suggested possible link between these two phenomena. We further confirmed link between CNP shape and free radical modulating activity to drive macrophage polarization through pharmacological inhibition of oxygen and nitrogen radicals. Overall, our results suggest that the biophysical characteristics such as shape of NPs play an important role in dictating macrophage polarization and can be exploited to design better delivery systems for drugs targeting macrophages.
Keywords: Cerium oxide, nanomaterial, free radical modulation, macrophage polarization, M1 and M2 phenotype, reactive oxygen species, reactive nitrogen species, macrophage priming, macrophage re-programming


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
RAKSHE, VISHALvpr4@pitt.eduvpr4
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairSant, Shilpashs149@pitt.edushs149
Committee MemberLi, Songsol4@pitt.edusol4
Empey, Kerrykme33@pitt.edukme33
Date: 23 April 2018
Date Type: Publication
Defense Date: 9 April 2018
Approval Date: 23 April 2018
Submission Date: 23 April 2018
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 78
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Keywords: Cerium oxide, nanomaterial, free radical modulation, macrophage polarization, M1 and M2 phenotype, reactive oxygen species, reactive nitrogen species, macrophage priming, macrophage re-programming
Date Deposited: 23 Apr 2018 15:01
Last Modified: 23 Apr 2018 15:01
URI: http://d-scholarship.pitt.edu/id/eprint/34381

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