ABSTRACT
Through its enormous surface, the lung provides a vast interface for exposure with inhaled particulates (Gehr et al. 1978). On the one hand, the interaction of nanosized particles with the human body, in particular with the respiratory tract as their main portal of entry, has become a fundamental topic in the eld of environmental/epidemiologic monitoring where inhalational exposure to ambient, combustion-derived particles is being increasingly recognized as an important cause of excess cardiovascular morbidity and mortality in areas with air pollution (Mills et al. 2009; Oberdorster 2001; Wichmann et al. 2000). On the other hand, in the area of innovative biomedical applications, the potential benets of manufactured nanoparticles (NPs) are increasingly being recognized. In particular, nanosized carriers have been proposed as promising novel diagnostic, therapeutic, and vaccination approaches for a variety of human diseases (Choi and Frangioni 2010; Foged et al. 2005; Nembrini et al. 2011; Zrazhevskiy et al. 2010). In particular, recent advances in both drug formulation and inhalation device design are creating new opportunities for inhaled drug and vaccine delivery as an alternative to oral or parenteral delivery methods (Tonnis et al. 2012). For example, in contrast to subcutaneous or intramuscular injection, pulmonary drug or vaccine delivery does not face drawbacks such as limited acceptance (needle phobia) and transmission of diseases by needle stick injury, and does not require trained health-care workers (Giudice and Campbell 2006; Kersten and Hirschberg 2004). Furthermore, pulmonary vaccine delivery is expected to be more efcient: the respiratory tract is continuously exposed to large amounts of inhaled and deposited airborne antigen, ranging from innocuous substances (e.g., house dust mite allergen) to potentially detrimental pathogens (e.g., bacteria, virus), which require an immune barrier consisting of several populations of immune cells (macrophages, dendritic cells [DCs], B cells, monocytes) in close proximity to the epithelium for protection (von Garnier et al. 2007). Those key players of pulmonary immunity provide promising targets for modulation by vaccines. The major advantages of aerosol delivery over other routes of administration
CONTENTS
10.1 Introduction ........................................................................................................................ 169 10.2 Deposition and Persistence in the Alveolar Region...................................................... 170 10.3 Translocation across the Air-Blood Tissue Barrier ....................................................... 173 10.4 Persistence in Blood Circulation ...................................................................................... 174 10.5 Conclusion .......................................................................................................................... 177 References ..................................................................................................................................... 177
are instant access, the high ratio of the drug deposited within the lungs noninvasively (Gautam et al. 2003); the large absorptive surface area (>140 m2); and the thin alveolar epithelium (0.1-0.2 μm) (Huang and Wang 2006; Niven 1995), rapid onset of drug absorption, comparatively lower enzymatic activity, and avoidance of the hepatic rst-pass effect (Misra 2010). For assessing the potential risks and benets of inhaled (nano)particles to human health, and to optimize the application of drugs or vaccines via the pulmonary route, two primary steps within the characterization of NPs are dosimetry and biokinetics (Kreyling et al. 2012). Dosimetry provides the essential base for the toxicological evaluation of any kind of NP (Kreyling et al. 2012). Furthermore, evaluation of the right dosimetry is indispensable in the development and characterization of biomedical NPs for diagnostic or therapeutic use. Biokinetics studies should be based on a broad range of administered particle doses. Special attention needs to be directed toward a too high particle burden applied, which can cause signicant biological and also toxic responses (e.g., overload of alveolar macrophages leading to neutrophilia in the alveolar lumen, or epithelial damage) and which may affect the biokinetics fate of the NPs (Kreyling et al. 2012). It is therefore essential that in a biokinetics study, a baseline situation showing physiological (healthy) condition is available for comparison. Hence, the amount of administered particles in biokinetics studies should be as low as possible to carefully analyze the translocation to target organs (Kreyling et al. 2012). However, since the focus of this chapter is on the translocation across the air-blood tissue barrier (i.e., in the alveolar region) of NPs, the emphasis of the present text will be put on the biokinetics toward systemic circulation rather than on NP dose metrics. The biokinetics of NPs depend, on the one hand, on particle characteristics such as size, shape, protein binding, agglomeration, hydrophobicity, and surface charge. On the other hand, biokinetics depend on the type of application to the human body and consequently on the interaction (i.e., translocation) of the NPs with the barriers present at the site of application. The crucial feature in the characterization of an NP entering the human respiratory tract is its potential to be interacting with the various parenchymal lung cells and in translocation. NPs may either get trapped within the diversity of biological barriers protecting the respiratory tract from harmful inhaled pathogen, or they may overcome existing barriers and enter the blood circulation. Entering the systemic circulation is a very crucial step in determining the fate of inhaled NPs because it allows particles direct translocation to secondary organs such as the liver, kidney, heart, and brain (Semmler-Behnke et al. 2007). This signicant step in NP translocation will be discussed in the present chapter, which will be subdivided into topics covering (i) deposition and persistence in the area close to the blood circulation (i.e., the alveoli), (ii) translocation to the respiratory capillaries, and (iii) persistence in the blood circulation.
