Robertson, James D. , Ward, Jon R. , ÁVILA OLÍAS, MARÍA MILAGROS, Battaglia, Giuseppe , Renshaw, Stephen A.
Si
J. Immunol.
Article
Científica
2
1
4.539
2.837
01/05/2017
000401135200027
2-s2.0-85018479687
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.
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; drug carrier; interleukin 8; polymersome; roscovitine; unclassified drug; cyclin dependent kinase; interleukin 8; liposome; microsphere; purine derivative; roscovitine; animal experiment; animal model; apoptosis; Article; biocompatibility; cell activation; cell viability; controlled study; cytokine release; cytosol; drug delivery system; embryo; endosome; human; human cell; in vitro study; in vivo study; inflammation; neutrophil; nonhuman; pH; transgenic zebrafish; zebra fish; animal; antagonists and inhibitors; cell culture; drug delivery system; drug effects; Fish Diseases; fluorescence microscopy; immunology; inflammation; leukocyte activation; metabolism; neutrophil; polymerization; transgenic a