ABSTRACT
Administration of therapeutics via inhalation provides an opportunity for direct delivery to the lung epithelium, and nanoparticles (NPs) have emerged as a versatile platform for this. Because of their size (<100 nm), inhaled NP can be effectively deposited in alveoli, where they interact with surfactant proteins and glycoproteins (Muhlfeld et al. 2008). Therapeutic effects at distal sites are dependent on translocation of NP into the underlying interstitium and subsequently into the circulation (Geiser and Kreyling 2010; Kato et al. 2003). However, this process is generally limited and strongly dependent on NP composition, dissolution, surface area, size, and shape (Da Silva et al. 2013; Madl and Pinkerton 2009). Most NP deposited in the lung are removed by macrophages located in the luminal airways and alveoli (Geiser 2010). These cells transport NP from the lung into ciliated airways and the larynx, where they are subject to mucociliary clearance. A less frequent clearance mechanism involves macrophage transport of NP
CONTENTS
6.1 Introduction ..........................................................................................................................85 6.2 Lung Macrophages ..............................................................................................................86 6.3 Uptake of NPs by Macrophages: Opsonization and Phagocytosis ..............................88 6.4 Nonphagocytic Uptake of NPs by Macrophages ............................................................ 89 6.5 Factors Controlling Uptake of NPs by Macrophages ..................................................... 89
6.5.1 Size ............................................................................................................................. 89 6.5.2 Shape ..........................................................................................................................90 6.5.3 Surface Properties ....................................................................................................90 6.5.4 Rigidity ...................................................................................................................... 91
6.6 Approaches to Reducing the Interaction of NPs with Macrophages ........................... 92 6.7 Examples of Macrophage Interactions with NPs ............................................................ 93
6.7.1 Metal Oxide NPs ...................................................................................................... 93 6.7.2 Carbon Nanobers (CNF) and CNT ..................................................................... 94 6.7.3 Silver NPs .................................................................................................................. 95 6.7.4 Silica NPs................................................................................................................... 95 6.7.5 Engineered NPs Used for Drug Delivery and Diagnosis .................................. 96
6.8 Summary and Conclusions ................................................................................................ 96 Acknowledgments ........................................................................................................................ 97 References ....................................................................................................................................... 97
through the interstitium into the tissue lymphatics and thoracic lymph nodes (Geiser 2010). Clearance of NP by lung macrophages poses a signicant barrier for both local and systemic delivery of therapeutics. Additionally, the interaction of NP with macrophages can cause cellular activation and/or toxicity, resulting in the release of cytotoxic/ pro-inammatory mediators that can cause collateral tissue injury (Roy et al. 2013a). For the potential therapeutic applications of NP to be realized, it is important to understand how NP can bypass lung macrophage defenses and limit inammatory responses.
