Cellular uptake and localization of inhaled gold nanoparticles in lungs of mice with chronic obstructive pulmonary disease

Abstract

BackgroundInhalative nanocarriers for local or systemic therapy are promising. Gold nanoparticles (AuNP) have been widely considered as candidate material. Knowledge about their interaction with the lungs is required, foremost their uptake by surface macrophages and epithelial cells.Diseased lungs are of specific interest, since these are the main recipients of inhalation therapy. We, therefore, used Scnn1b-transgenic (Tg) mice as a model of chronic obstructive pulmonary disease (COPD) and compared uptake and localization of inhaled AuNP in surface macrophages and lung tissue to wild-type (Wt) mice.MethodsScnn1b-Tg and Wt mice inhaled a 21-nm AuNP aerosol for 2 h. Immediately (0 h) or 24 h thereafter, bronchoalveolar lavage (BAL) macrophages and whole lungs were prepared for stereological analysis of AuNP by electron microscopy.ResultsAuNP were mainly found as singlets or small agglomerates of ≤ 100 nm diameter, at the epithelial surface and within lung-surface structures. Macrophages contained also large AuNP agglomerates (> 100 nm). At 0 h after aerosol inhalation, 69.2±4.9% AuNP were luminal, i.e. attached to the epithelial surface and 24.0±5.9% in macrophages in Scnn1b-Tg mice. In Wt mice, 35.3±32.2% AuNP were on the epithelium and 58.3±41.4% in macrophages. The percentage of luminal AuNP decreased from 0 h to 24 h in both groups. At 24 h, 15.5±4.8% AuNP were luminal, 21.4±14.2% within epithelial cells and 63.0±18.9% in macrophages in Scnn1b-Tg mice. In Wt mice, 9.5±5.0% AuNP were luminal, 2.2±1.6% within epithelial cells and 82.8±0.2% in macrophages. BAL-macrophage analysis revealed enhanced AuNP uptake in Wt animals at 0 h and in Scnn1b-Tg mice at 24 h, confirming less efficient macrophage uptake and delayed clearance of AuNP in Scnn1b-Tg mice.ConclusionsInhaled AuNP rapidly bound to the alveolar epithelium in both Wt and Scnn1b-Tg mice. Scnn1b-Tg mice showed less efficient AuNP uptake by surface macrophages and concomitant higher particle internalization by alveolar type I epithelial cells compared to Wt mice. This likely promotes AuNP depth translocation in Scnn1b-Tg mice, including enhanced epithelial targeting. These results suggest AuNP nanocarrier delivery as successful strategy for therapeutic targeting of alveolar epithelial cells and macrophages in COPD.

Nanoparticle uptake by airway phagocytes after fungal spore challenge in murine allergic asthma and chronic bronchitis

“…Thus, it is likely that single AuNP attach to the cell membrane, which is then used by the macrophages to phagocytose larger-sized foreign material, including fungal spores. This “unintentional” uptake of NP correlates with data from previous inhalation studies in rodents using TiO 2 and Au nanoparticles of approximately 20 nm diameter [11,18]. In the latter study, fast attachment of AuNP to lung cells has been demonstrated [18].…”

“…In COPD, phagocytic activity of surface macrophages seems to be decreased independent of particle size; e.g. reduced uptake of apoptotic cells has been reported [17], and we recently obtained evidence for delayed and less efficient uptake of inhaled 20-nm AuNP in Scnn1b-Tg mice with COPD-like lung disease [18]. Contrary to the consequences of harmful NP, impaired phagocytosis resulting in a prolonged residence time of deposited AuNP on the epithelial surface may be favorable in case of therapeutic targeting of the lung parenchyma by inhaled aerosols.…”

Medical nanoparticles for next generation drug delivery to the lungs

“…Particle uptake and localisation is also dependent on disease type. Inhaled gold particles were taken up less by surface macrophages but at a higher rate by alveolar type I epithelial cells in Scnn1b-transgenic COPD mice compared to wild-type mice [67].…”

Quantitative immunocytochemistry at the ultrastructural level: a stereology-based approach to molecular nanomorphomics

“…Although the presently worked examples are all synthetic (rather than based on real experimental data), the methods that they illustrate have been applied in a wide variety of studies involving bacteria, viruses and animal and plant cells and tissues (for a list of references, see Mayhew 2011). Moreover, they have been adopted in areas other than ICC in order to analyse, for instance, spatial distributions of nanoparticles within cells/ tissues (Mühlfeld et al 2007(Mühlfeld et al , 2008Geiser et al 2013) and the association of viruses with the symbiotic pair of Paramecium and Chlorella (Yashchenko et al 2012). In principle, they could also be applied in immuno-quantum dot cytochemistry (e.g., Nisman et al 2012;Killingsworth et al 2012).…”