Optical tweezers reveal relationship between microstructure and nanoparticle penetration of pulmonary mucus

Abstract

In this study, the mobility of nanoparticles in mucus and similar hydrogels as model systems was assessed to elucidate the link between microscopic diffusion behavior and macroscopic penetration of such gels. Differences in particle adhesion to mucus components were strongly dependent on particle coating. Particles coated with 2 kDa PEG exhibited a decreased adhesion to mucus components, whereas chitosan strongly increased the adhesion. Despite such mucoinert properties of PEG, magnetic nanoparticles of both coatings did not penetrate through native respiratory mucus, resisting high magnetic forces (even for several hours). However, model hydrogels were, indeed, penetrated by both particles in dependency of particle coating, obeying the theory of particle mobility in an external force field. Comparison of penetration data with cryogenic scanning EM images of mucus and the applied model systems suggested particularly high rigidity of the mucin scaffold and a broad pore size distribution in mucus as reasons for the observed particle immobilization. Active probing of the rigidity of mucus and model gels with optical tweezers was used in this context to confirm such properties of mucus on the microscale, thus presenting the missing link between micro-and macroscopical observations. Because of high heterogeneity in the size of the voids and pores in mucus, on small scales, particle mobility will depend on adhesive or inert properties. However, particle translocation over distances larger than a few micrometers is restricted by highly rigid structures within the mucus mesh.forced penetration | pulmonary drug delivery | cryoelectronmicroscopy

A Model for the Transient Subdiffusive Behavior of Particles in Mucus

“…In our study, we characterize the transient subdiffusive behavior by determining the time-dependent anomaly exponent aðtÞ from the dimensionless logarithmic derivative of the MSD(t). This is given as follows (26,36,37): 6) and is shown in Fig. 3 B.…”

“…To overcome this biological barrier caused by some novel inhalation pharmaceuticals, functionalized and nontoxic nanocarriers can be used. Inspired from viruses, nanosized particles with neutrally charged coatings such as polyethylene glycol (PEG) can efficiently penetrate the mucus layer in contrast to charged particles (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12).…”

Methods to determine the interactions of micro- and nanoparticles with mucus

“…Several sources of mucus have been used for permeation / transport studies ranging from native mucus gels, scraped gently from the surface of gastrointestinal mucosa of the pig [4,5] to horse bronchial mucus [6]. Mucins are the major gel forming components of mucus gels which have a major role in governing the pore size in a mucus gel so many permeation studies have used mucins to mimic the mucus gel barrier [7,8].…”

Rotation-Facilitated Rapid Transport of Nanorods in Mucosal Tissues

“…Mucus is a tenacious mesh structure with a thickness ranging from tens to hundreds of microns and an average pore size in the range of hundreds of nanometers 4 . Small hydrophilic molecules can freely diffuse through this barrier while particles, especially foreign particles, are excluded in cases where the particle size is larger than the average pore size [5][6][7][8][9] . The trapped particles are then quickly washed away by the microflows of the mucus layer.…”