期刊
JOURNAL OF CONTROLLED RELEASE
卷 316, 期 -, 页码 393-403出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2019.09.012
关键词
Pulmonary delivery; Nanoparticle; Microparticle; Phagocytosis; Controlled release; Multi-Stage carriers; Nano-In-Microgel; Microgel
资金
- National Science Foundation [NSF DMR 1417137]
- Marcus Center for Therapeutic Cell Characterization and Manufacturing (MC3M) at Georgia Tech
- Georgia Tech Foundation
- Georgia Tech Research Alliance
- Center for Cystic Fibrosis Airways Disease Research and Children's Healthcare of Atlanta
- NIH/NIGMS [T32GM008433]
- NSF [DGE-1650044]
Although the lung is an obvious target for site-specific delivery of many therapeutics for respiratory airway diseases such as asthma, COPD, and cystic fibrosis, novel strategies are needed to avoid key physiologic barriers for efficient delivery and controlled release of therapeutics to the lungs. Specifically, deposition into the deep lung requires particles with a 1- 5 mu m aerodynamic diameter; however, particles with a geometric diameter less than 6 mu m are rapidly cleared by alveolar macrophages. Additionally, epithelial, endothelial, and fibroblast cells prefer smaller (< 300 nm) nanoparticles for efficient endocytosis. Here we address these contradictory design requirements by using a nanoparticle-inside-microgel system (Nano-in-Microgel). Using an improved maleimidethiol based Michael Addition during (water-in-oil) Emulsion (MADE) method, we fabricated both trypsin-responsive and neutrophil elastase-responsive polymeric Nano-in-Microgel to show the versatility of the system in easily exchanging enzyme-responsive crosslinkers for disease-specific proteases. By varying the initial macromer concentration, from 20 to 50% w/v, the size distribution means ranged from 4 - 8 mu m enzymatic degradation of the microgels is within 30 min, and in vitro macrophage phagocytosis is lower for the higher % w/v. We further demonstrated that in vivo lung delivery of the multi-stage carriers through the pulmonary route yields particle retention up to several hours and followed by clearance within in naive mice. Our results provide a further understanding of how enzymatically-degradable multi-stage polymeric carriers can be used for pulmonary drug delivery.
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