Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA.
Center for Immunoengineering, Georgia Institute of Technology, Atlanta, Georgia, USA.
JCI Insight. 2019 Dec 5;4(23):131468. doi: 10.1172/jci.insight.131468.
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-in-microgel 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.
肺部药物输送为靶向下呼吸道炎症提供了独特的机会，下呼吸道炎症的特征通常是大量中性粒细胞从血液中募集。然而，缺乏针对气道中性粒细胞功能的特定疗法，并且必须克服许多困难才能实现针对肺部炎症的治疗效果，特别是药物疏水性、黏液纤毛和巨噬细胞依赖性清除以及高细胞外蛋白酶负担。在这里，我们提出了一种多阶段、空气动力学有利的输送平台，该平台利用细胞外蛋白酶解作用的优势，将纳米颗粒嵌入的疏水性药物递送至下呼吸道中的中性粒细胞。我们的设计包括一个自我调节的纳米颗粒-微凝胶系统，其中微凝胶的激活是由细胞外弹性蛋白酶触发的（由炎症中性粒细胞脱颗粒），并将纳米颗粒加载到Nexinhib20 中，这是一种有效的中性粒细胞脱颗粒抑制剂。成功地将 Nexinhib20 递送至气道和中性粒细胞中，通过抑制中性粒细胞募集和脱颗粒、气道和全身隔室中的促炎细胞因子产生以及肺液中存在中性粒细胞衍生的病理性细胞外囊泡，促进了炎症反应的消退。我们的研究结果展示了一个新的平台，该平台克服了肺部药物输送中的挑战，并允许根据特定疾病的蛋白酶足迹进行定制。
