Abstract
Pulmonary delivery of nanomedicines has been extensively studied in recent years because of their enhanced biocompatibility, sustained-release properties, and surface modification capability. The lung as a target also offers many advantages over other routers, such as large surface area, noninvasive, quick therapeutic onset, and avoiding first-pass metabolism. However, nanoparticles smaller than 0.26 µm typically escape phagocytosis and remain in the alveoli for a long time, leading to particle accumulation and invoking tissue responses. It is imperative to understand the behavior and fates of inhaled nanoparticles in the alveoli to reliably assess therapeutic outcomes of nanomedicines or health risk of environmental toxins. The objective of this study is to numerically investigate nanoparticle deposition in a duct-alveolar model with varying sizes of inter-alveolar septal apertures (pores). A discrete phase Lagrangian model was implemented to track nanoparticle trajectories under the influence of rhythmic wall expansion and contraction. Both temporal and spatial dosimetry in the alveoli were computed. Wall motions are essential for nanoparticles to penetrate the acinar region and deposit in the alveoli. The level of aerosol irreversibility (i.e., mixing of inhaled nanoparticles with residual air in the alveolar airspace) is determined by the particle diffusivity, which in turn, dictates the fraction of particles being exhaled out. When deposition in the upper airways was not considered, high alveolar deposition rates (74–95%) were predicted for all nanoparticles considered (1–1000 nm), which were released into the alveoli at the beginning of the inhalation. The pore size notably affects the deposition pattern of inhaled nanoparticles but exerts a low impact upon the total deposition fractions. This finding indicates that consistent pulmonary doses of nanomedicine are possible in emphysema patients if breathing maneuver with the same tidal volume can be performed.
Highlights
The integration of nanoscience and inhalation drug delivery offers exciting potentials to enhance the targeting, release, diagnostic, and therapeutic outcomes of drugs [1,2,3]
Various nanomedicines have been devised in recent years for local and systemic treatments of diseases, which include small molecules, macromolecules, peptide, protein, and genes
It is well accepted that the deposition mechanics of nanoparticles in the acinar region are diffusion and gravitational sedimentation
Summary
The integration of nanoscience and inhalation drug delivery offers exciting potentials to enhance the targeting, release, diagnostic, and therapeutic outcomes of drugs [1,2,3]. Targeted pulmonary delivery of genes to the disease site offers great potential for the treatment of genetic lung disorders, such as alpha-1-antitrypsin deficiency [7,8], cystic fibrosis [9], and asthma [10]. Particles 260 nm or smaller eludes the phagocytosis and cannot be cleared from the pulmonary region [15]. Such nanocarriers can remain in the lungs for up to 700 days [16], which either remain in the alveolar cells or translocate into the interstitium, causing long-term accumulations and invoking toxicity issues. It is critical to understand the behavior and fate of inhaled nanoparticles inside the alveoli, to reliably establish the dose-outcome relationship for either inhaled therapeutic pharmaceuticals or environmental toxins
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