Drug carrier nanoparticles that penetrate human chronic rhinosinusitis mucus

Abstract

No effective therapies currently exist for chronic rhinosinusitis (CRS), a persistent inflammatory condition characterized by the accumulation of highly viscoelastic mucus (CRSM) in the sinuses. Nanoparticle therapeutics offer promise for localized therapies for CRS, but must penetrate CRSM in order to avoid washout during sinus cleansing and to reach underlying epithelial cells. Prior research has not established whether nanoparticles can penetrate the tenacious CRSM barrier, or instead become trapped. Here, we first measured the diffusion rates of polystyrene nanoparticles and the same nanoparticles modified with muco-inert polyethylene glycol (PEG) coatings in fresh, minimally perturbed CRSM collected during endoscopic sinus surgery from CRS patients with and without nasal polyp. We found that uncoated polystyrene particles, previously shown to be mucoadhesive, were immobilized in all CRSM samples tested. In contrast, densely PEGylated particles as large as 200 nm were able to readily penetrate all CRSM samples from patients with CRS alone, and nearly half of CRSM samples from patients with nasal polyp. Based on the mobility of different sized PEGylated particles, we estimate the average pore size of fresh CRSM to be at least 150 ± 50 nm. Guided by these studies, we formulated mucus-penetrating particles (MPP) composed of PLGA and Pluronics, two materials with a long history of safety and use in humans. We showed that biodegradable MPP are capable of rapidly penetrating CRSM at average speeds up to only 20-fold slower than their theoretical speeds in water. Our findings strongly support the development of mucus-penetrating nanomedicines for the treatment of CRS.

Complex Fluids and Soft Structures in the Human Body

“…Note that the results from these studies imply that the mucus gel network has pores that are larger than the diameter of many known viruses [168]. It is clear that mucus employs methods other than obstruction to prevent viruses from infecting [150], c [156], d [169] mucosal surfaces, indicating that mucus is not just a steric barrier to deposited particulates. Namely, mucus is also an effective "adhesive" that can immobilize particles by hydrophobic and electrostatic interactions and hydrogen bonding [145].…”

“…MSD is calculated as 20) where r(t) is the position of the particle at time t, τ is the lag time between the two positions taken by the particle used to calculate the displacement Δ r, and the average ··· designates a time average over t and/or an ensemble-average over several trajectories. Reported values of MSD in mucus [73,75,[154][155][156] show a sub-diffusive MSD scaling over an intermediate dynamic range,…”

Direct Determination of Chitosan–Mucin Interactions Using a Single-Molecule Strategy: Comparison to Alginate–Mucin Interactions

“…Added to this, mucus provides a substantial barrier to the diffusion of large, charged and lipophilic entities, which can dramatically reduce diffusion rates [87][88][89]. Indeed, these issues have resulted in increasing interest in the development of muco-inert carrier systems in the form of mucus-penetrating particles that avoid interaction with mucus and thus experience a lower diffusion barrier [84,[90][91][92][93].…”

Nanotechnology-based drug delivery in mucosal immune diseases: hype or hope?

“…Protective mucus usually traps and removes foreign particles from the mucosal surface. Biodegradable polymeric particles of larger size (200 nm) have been shown to be capable of rapidly penetrating healthy (e.g., cervicovaginal 14 ) or diseased (e.g., chronic rhinosinusitis 15 ) human mucus barriers. During this process, however, nanoparticles can alter the microstructure of the mucus barrier, 16 but the functional impact of this observation remains to be examined in vivo (e.g., do nanoparticle-induced "holes" disrupt the mucus barrier, allowing bacterial translocation?).…”