Prevention of vascular inflammation by nanoparticle targeting of adherent neutrophils

Abstract

Inflammatory diseases such as acute lung injury and ischaemic tissue injury are caused by the adhesion of a type of white blood cell—polymorphonuclear neutrophils—to the lining of the circulatory system or vascular endothelium and unchecked neutrophil transmigration1,2. Nanoparticle-mediated targeting of activated neutrophils on vascular endothelial cells at the site of injury may be a useful means of directly inactivating neutrophil transmigration and hence mitigating vascular inflammation3. Here, we report a method employing drug-loaded albumin nanoparticles, which efficiently deliver drugs into neutrophils adherent to the surface of the inflamed endothelium. Using intravital microscopy of tumour necrosis factor-α-challenged mouse cremaster post-capillary venules, we demonstrate that fluorescently tagged albumin nanoparticles are largely internalized by neutrophils adherent to the activated endothelium via cell surface Fcɣ receptors. Administration of albumin nanoparticles loaded with the spleen tyrosine kinase inhibitor, piceatannol, which blocks ‘outside-in’ β2 integrin signalling in leukocytes, detached the adherent neutrophils and elicited their release into the circulation. Thus, internalization of drug-loaded albumin nanoparticles into neutrophils inactivates the pro-inflammatory function of activated neutrophils, thereby offering a promising approach for treating inflammatory diseases resulting from inappropriate neutrophil sequestration and activation.

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Figure 1: Uptake of albumin nanoparticles by adherent neutrophils in venules.
Figure 2: Characteristics of internalization properties of different types of albumin nanoparticle.
Figure 3: Contribution of FcγRIII mechanism in mediating albumin nanoparticle internalization.
Figure 4: Therapeutic activity of albumin nanoparticles in vascular inflammation and lung injury models.

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Acknowledgements

This work was supported by grant no. 11SDG7490013 from the American Heart Association and National Institutes of Health grants K25HL111157 to Z.W., R01 HL109439 to J.C. and P01 P01HL77806 to A.B.M.

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Contributions

Z.W., J.C. and A.B.M. designed the experiments and analysed the data. Z.W. and J.L. carried out the experiments. Z.W., J.C. and A.B.M. wrote the manuscript.

Corresponding author

Correspondence to Asrar B. Malik.

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The authors declare no competing financial interests.

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Wang, Z., Li, J., Cho, J. et al. Prevention of vascular inflammation by nanoparticle targeting of adherent neutrophils. Nature Nanotech 9, 204–210 (2014). https://doi.org/10.1038/nnano.2014.17

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