title: Targeting Neutrophilic Inflammation Using Polymersome-Mediated Cellular Delivery.
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.
authors.affiliation: Department of Biomedical Science, University College London, London WC1E 6BT, United Kingdom.|Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom.|The Bateson Centre, The University of Sheffield, Western Bank, Sheffield S10 2TN, United Kingdom.
authors.forename: James D
authors.identifier: 0000-0002-9961-0073
authors.initials: JD
authors.lastname: Robertson
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom.|The Bateson Centre, The University of Sheffield, Western Bank, Sheffield S10 2TN, United Kingdom.
authors.forename: Jon R
authors.identifier: 0000-0001-9453-3147
authors.initials: JR
authors.lastname: Ward
authors.affiliation: Department of Biomedical Science, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Milagros
authors.initials: M
authors.lastname: Avila-Olias
authors.affiliation: Department of Chemistry, University College London, London WC1E 6BT, United Kingdom; and s.a.renshaw@sheffield.ac.uk g.battaglia@ucl.ac.uk.|The Medical Research Council/University College London Centre for Molecular and Medical Virology, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Giuseppe
authors.identifier: 0000-0003-3349-6770
authors.initials: G
authors.lastname: Battaglia
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom; s.a.renshaw@sheffield.ac.uk g.battaglia@ucl.ac.uk.|The Bateson Centre, The University of Sheffield, Western Bank, Sheffield S10 2TN, United Kingdom.
authors.forename: Stephen A
authors.identifier: 0000-0003-1790-1641
authors.initials: SA
authors.lastname: Renshaw
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D016503:Drug Delivery Systems; D005393:Fish Diseases / Q000188:drug therapy*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D016209:Interleukin-8 / Q000378:metabolism; D008081:Liposomes / Q000627:therapeutic use; D008856:Microscopy, Fluorescence; D008863:Microspheres; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D058105:Polymerization; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use*; D000077546:Roscovitine; D015027:Zebrafish
chemical_list: D016209:Interleukin-8; D008081:Liposomes; D011687:Purines; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases