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Nanoparticle clearance is governed by Th1/Th2 immunity and strain background
Stephen W. Jones, … , Joseph M. DeSimone, James E. Bear
Stephen W. Jones, … , Joseph M. DeSimone, James E. Bear
Published June 17, 2013
Citation Information: J Clin Invest. 2013;123(7):3061-3073. https://doi.org/10.1172/JCI66895.
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Research Article Immunology

Nanoparticle clearance is governed by Th1/Th2 immunity and strain background

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Abstract

Extended circulation of nanoparticles in blood is essential for most clinical applications. Nanoparticles are rapidly cleared by cells of the mononuclear phagocyte system (MPS). Approaches such as grafting polyethylene glycol onto particles (PEGylation) extend circulation times; however, these particles are still cleared, and the processes involved in this clearance remain poorly understood. Here, we present an intravital microscopy–based assay for the quantification of nanoparticle clearance, allowing us to determine the effect of mouse strain and immune system function on particle clearance. We demonstrate that mouse strains that are prone to Th1 immune responses clear nanoparticles at a slower rate than Th2-prone mice. Using depletion strategies, we show that both granulocytes and macrophages participate in the enhanced clearance observed in Th2-prone mice. Macrophages isolated from Th1 strains took up fewer particles in vitro than macrophages from Th2 strains. Treating macrophages from Th1 strains with cytokines to differentiate them into M2 macrophages increased the amount of particle uptake. Conversely, treating macrophages from Th2 strains with cytokines to differentiate them into M1 macrophages decreased their particle uptake. Moreover, these results were confirmed in human monocyte–derived macrophages, suggesting that global immune regulation has a significant impact on nanoparticle clearance in humans.

Authors

Stephen W. Jones, Reid A. Roberts, Gregory R. Robbins, Jillian L. Perry, Marc P. Kai, Kai Chen, Tao Bo, Mary E. Napier, Jenny P.Y. Ting, Joseph M. DeSimone, James E. Bear

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Figure 1

IVM-based assay for screening nanoparticle clearance rates in live animals.

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IVM-based assay for screening nanoparticle clearance rates in live anima...
(A) A blood vessel is positioned in the center of the scan area. (B) Cartoon showing the orientation of the mouse, the positioning of the objective, and the region of the mouse ear imaged. (C) Movies were analyzed with ImageJ software by selecting a straight-line region of interest (ROI) in the large vein, and the average fluorescence intensity for each time point was calculated. Scale bar: 50 μm. (D) A representative fluorescence versus time plot of nanoparticle clearance. Marked region represents the AUC, which is calculated to determine the relative exposure of the particles to blood.
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