PUBLICATION
Targeting Neutrophilic Inflammation Using Polymersome-Mediated Cellular Delivery
- Authors
- Robertson, J.D., Ward, J.R., Avila-Olias, M., Battaglia, G., Renshaw, S.A.
- ID
- ZDB-PUB-170316-12
- Date
- 2017
- Source
- Journal of immunology (Baltimore, Md. : 1950) 198(9): 3596-3604 (Journal)
- Registered Authors
- Renshaw, Steve A., Robertson, James
- Keywords
- none
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Apoptosis/drug effects
- Cells, Cultured
- Cyclin-Dependent Kinases/antagonists & inhibitors
- Drug Delivery Systems
- Fish Diseases/drug therapy*
- Humans
- Inflammation/drug therapy*
- Interleukin-8/metabolism
- Liposomes/therapeutic use
- Microscopy, Fluorescence
- Microspheres*
- Neutrophil Activation/drug effects
- Neutrophils/drug effects*
- Neutrophils/immunology
- Polymerization
- Purines/pharmacology
- Purines/therapeutic use*
- Zebrafish
- PubMed
- 28289157 Full text @ J. Immunol.
Citation
Robertson, J.D., Ward, J.R., Avila-Olias, M., Battaglia, G., Renshaw, S.A. (2017) Targeting Neutrophilic Inflammation Using Polymersome-Mediated Cellular Delivery. Journal of immunology (Baltimore, Md. : 1950). 198(9):3596-3604.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping