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 in a number of human mucus secretions, 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 estimated the average pore size of fresh CRSM to be at least 150 ± 50 nm. Guided by these studies, we formulated mucus-penetrating particles composed of poly(lactide-co-glycolide) (PLGA) and Pluronics, two materials with a long history of safety and use in humans. We showed that these biodegradable particles 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.

Figure 1

Transport of different sized uncoated (PS-COOH) and minimally mucoadhesive PEG-coated (PS-PEG) latex particles in fresh, undiluted human chronic sinusitis mucus (CRSM). Representative trajectories of (A) 200 nm PS-COOH, and (B) 100 nm, (C) 200 nm and (D) 500 nm PS-PEG in CRSM from 20 s movies. The particle traces reflect effective diffusivities within one s.e.m. of the ensemble mean at a time scale of 1 s. (E) Ensemble-averaged geometric mean square displacements (<MSD>) as a function of time scale. Data represent four independent experiments, with n > 100 particles per experiment.

Figure 2

Distributions of the logarithms of individual particle effective diffusivities (Deff) at a time scale of 1 s for (A) 100 nm PS-PEG, (B) 200 nm PS-PEG, (C) 500 nm PS-PEG and (D) 200 nm PS-COOH particles.

Figure 3

Distribution of effective pore sizes in human chronic sinusitis mucus estimated by obstruction scaling model, with average pore size ~150 ± 50 nm.

Figure 4

Transport of biodegradable polymeric nanoparticles composed of poly(lactide-co-glycolide (PLGA) in CRSM. Representative trajectories of (A) uncoated (PLGA) and (B) Pluronic F127-coated (PLGA/F127) PLGA particles in CRSM traced over 20 s. The particle traces reflect effective diffusivities within one s.e.m. of the ensemble mean. (C) Ensemble-averaged geometric mean square displacements (<MSD>) as a function of time scale. Data represent three independent experiments with n > 150 particles per experiment. (D) Distributions of the logarithms of individual particle effective diffusivities (Deff) at a time scale of 1 s. (E) Fractions of PLGA and PLGA/F127 undergoing diffusive motion in CRSM. Bars represent standard errors. * denotes statistical significance (p<0.05).

Figure 5

Ensemble-averaged geometric mean square displacements () at a time scale of 1 s for 200 nm PS-PEG (cross mark x) and ~200 nm PLGA/F127 (closed circle •) particles for (A) each individual CRSM sample tested, and (B) CRSM samples grouped by whether the patient has nasal polyps (+NP) or not (−NP).