Neutrophil-targeted, protease-activated pulmonary drug delivery blocks airway and systemic inflammation

• Type of Material: Article
• Authors: Joscelyn C. Mejias, Georgia Institute of Technology; Osric A. Forrest, Emory University; Camilla Margaroli, Emory University; David A. Frey Rubio, Georgia Institute of Technology; Liliana Viera, University of Alabama Birmingham; Jindong Li, University of Alabama Birmingham; Xin Xu, University of Alabama Birmingham; Amit Gaggar, University of Alabama Birmingham; Rabindra Tirouvanziam, Emory University; Krishnendu Roy, Emory University
• Language: English
• Date: 2019-12-05
• Publisher: The American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2019 American Society for Clinical Investigation. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1172/jci.insight.131468
• Title of Journal or Parent Work: JCI Insight
• Volume: 4
• Issue: 23
• Start Page: 1
• End Page: 9
• Grant/Funding Information: This work was supported by the Center for Cystic Fibrosis Airways Disease Research pilot grant and Children’s Healthcare of Atlanta (AG, RT, KR), Robert A. Milton Chair funds (KR), funds from the Georgia Tech Foundation (KR), NSF DMR 1417137 (KR), NIH/National Institute of General Medical Sciences–sponsored Cell and Tissue Engineering Biotechnology Training Program T32GM008433 (JCM), NIH R01 HL102371 (AG), NIH R01 HL126603 (RT), NSF Graduate Research Fellowship DGE-1650044 (JCM), and CF@LANTA Research Development Program Fellowship (CM) as funded by the US Cystic Fibrosis Foundation (MCCART15R0).
• Keywords: Research & Experimental Medicine; Life Sciences & Biomedicine; Disease; Medicine, Research & Experimental; Science & Technology
• Research Categories: Engineering, Biomedical; Health Sciences, Immunology; Health Sciences, Medicine and Surgery

Abstract

Pulmonary drug delivery presents a unique opportunity to target lower airway inflammation, which is often characterized by the massive recruitment of neutrophils from blood. However, specific therapies are lacking modulation of airway neutrophil function, and difficult challenges must be overcome to achieve therapeutic efficacy against pulmonary inflammation, notably drug hydrophobicity, mucociliary and macrophage-dependent clearance, and high extracellular protease burden. Here, we present a multistage, aerodynamically favorable delivery platform that uses extracellular proteolysis to its advantage to deliver nanoparticle-embedded hydrophobic drugs to neutrophils within the lower airways. Our design consists of a self-regulated nanoparticle-inmicrogel system, in which microgel activation is triggered by extracellular elastase (degranulated by inflammatory neutrophils), and nanoparticles are loaded with Nexinhib20, a potent neutrophil degranulation inhibitor. Successful in vivo delivery of Nexinhib20 to the airways and into neutrophils promoted resolution of the inflammatory response by dampening neutrophil recruitment and degranulation, proinflammatory cytokine production in both airway and systemic compartments, as well as the presence of neutrophil-derived pathological extracellular vesicles in the lung fluid. Our findings showcase a new platform that overcomes challenges in pulmonary drug delivery and allows customization to match the proteolytic footprint of given diseases.