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Targeting Neutrophilic Inflammation Using Polymersome-Mediated Cellular Delivery

Robertson, JD; Ward, JR; Avila-Olias, M; Battaglia, G; Renshaw, SA; (2017) Targeting Neutrophilic Inflammation Using Polymersome-Mediated Cellular Delivery. The Journal of Immunology , 198 (9) pp. 3596-3604. 10.4049/jimmunol.1601901. Green open access

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Abstract

Neutrophils are key effector cells in inflammation and play an important role in neutralizing invading pathogens. During inflammation resolution, neutrophils undergo apoptosis before they are removed by macrophages, but if apoptosis is delayed, neutrophils can cause extensive tissue damage and chronic disease. Promotion of neutrophil apoptosis is a potential therapeutic approach for treating persistent inflammation, yet neutrophils have proven difficult cells to manipulate experimentally. In this study, we deliver therapeutic compounds to neutrophils using biocompatible, nanometer-sized synthetic vesicles, or polymersomes, which are internalized by binding to scavenger receptors and subsequently escape the early endosome through a pH-triggered disassembly mechanism. This allows polymersomes to deliver molecules into the cell cytosol of neutrophils without causing cellular activation. After optimizing polymersome size, we show that polymersomes can deliver the cyclin-dependent kinase inhibitor (R)-roscovitine into human neutrophils to promote apoptosis in vitro. Finally, using a transgenic zebrafish model, we show that encapsulated (R)-roscovitine can speed up inflammation resolution in vivo more efficiently than the free drug. These results show that polymersomes are effective intracellular carriers for drug delivery into neutrophils. This has important consequences for the study of neutrophil biology and the development of neutrophil-targeted therapeutics.

Type: Article
Title: Targeting Neutrophilic Inflammation Using Polymersome-Mediated Cellular Delivery
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.4049/jimmunol.1601901
Publisher version: http://dx.doi.org/10.4049/jimmunol.1601901
Language: English
Additional information: This article is distributed under the terms of the CC BY 4.0 Unported license.
Keywords: Animals, Animals, Genetically Modified, Apoptosis, Cells, Cultured, Cyclin-Dependent Kinases, Drug Delivery Systems, Fish Diseases, Humans, Inflammation, Interleukin-8, Liposomes, Microscopy, Fluorescence, Microspheres, Neutrophil Activation, Neutrophils, Polymerization, Purines, Zebrafish
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: http://discovery.ucl.ac.uk/id/eprint/1550626
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