Critical Determinants of Uptake and Translocation of Nanoparticles by the Human Pulmonary Alveolar Epithelium

Abstract

The ability to manipulate the size and surface properties of nanomaterials makes them a promising vector for improving drug delivery and efficacy. Inhalation is a desirable route of administration as nanomaterials preferentially deposit in the alveolar region, a large surface area for drug absorption. However, as yet, the mechanisms by which particles translocate across the alveolar epithelial layer are poorly understood. Here we show that human alveolar type I epithelial cells internalize nanoparticles, whereas alveolar type II epithelial cells do not, and that nanoparticles translocate across the epithelial monolayer but are unable to penetrate the tight junctions between cells, ruling out paracellular translocation. Furthermore, using siRNA, we demonstrate that 50 nm nanoparticles enter largely by passive diffusion and are found in the cytoplasm, whereas 100 nm nanoparticles enter primarily via clathrin- and also caveolin-mediated endocytosis and are found in endosomes. Functionalization of nanoparticles increases their uptake and enhances binding of surfactant which further promotes uptake. Thus, we demonstrate that uptake and translocation across the pulmonary epithelium is controlled by alveolar type I epithelial cells, and furthermore, we highlight a number of factors that should be considered when designing new nanomedicines in order to improve drug delivery to the lung.

Oral uptake of nanoparticles: human relevance and the role of in vitro systems

“…Translocation was inversely related to particle size and constant up to 100 ng/cm 2 . Fifty-nm polystyrene particles were transported to 3 % (unmodified) and 8 % (carboxylated) across TT1 alveolar epithelial cell monolayers (Thorley et al 2014). No transport has been detected for the 100-nm particles assessed in parallel in this study.…”

Static and Dynamic Microscopy of the Chemical Stability and Aggregation State of Silver Nanowires in Components of Murine Pulmonary Surfactant

“…In a recent study, human LLF increased the uptake of polystyrene NPs by human alveolar epithelial cells, regardless of NP size or surface modification. 43 Moreover, coating MWCNTs 44 or SWCNTs 45 with lipids evoked an increase in intracellular reactive oxygen species (ROS) production.…”

Efficient delivery of ursolic acid by poly(N-vinylpyrrolidone)-block-poly (ε-caprolactone) nanoparticles for inhibiting the growth of hepatocellular carcinoma in vitro and in vivo

“…25,26 However, a recent publication reported that 50 nm nanoparticles enter largely by passive diffusion and are found in the cytoplasm, whereas 100 nm nanoparticles enter primarily via clathrinand also caveolin-mediated endocytosis and are found in endosomes. 27 The contradiction here needs further study to elucidate the possible mechanisms of cellular uptake of nanoparticles. Nevertheless, since the T/C% is closely related to the intracellular accumulation of drugs, drug-loaded nanoparticles could reach relatively higher concentration in tumor cells due to endocytosis.…”