Robertson, J.D., Ward, J.R., Avila-Olias, M. et al. (2 more authors) (2017) Targeting Neutrophilic Inflammation using Polymersome-Mediated Cellular Delivery. Journal of Immunology, 189 (9). pp. 3596-3604. ISSN 0022-1767
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2017 The Authors This article is distributed under the terms of the CC BY 4.0 Unported license (https://creativecommons.org/licenses/by/4.0/). |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Infection, Immunity and Cardiovascular Disease The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number MEDICAL RESEARCH COUNCIL MR/M004864/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 15 Mar 2017 10:42 |
Last Modified: | 22 May 2017 15:30 |
Published Version: | https://doi.org/10.4049/jimmunol.1601901 |
Status: | Published |
Publisher: | American Association of Immunologists |
Refereed: | Yes |
Identification Number: | 10.4049/jimmunol.1601901 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:113130 |