Probing the interaction of nanoparticles with mucin for drug delivery applications using dynamic light scattering

Abstract

Drug delivery via the eye, nose, gastrointestinal tract and lung are of great interest as they represent patient-compliant and facile methods to administer drugs. However, for a drug to reach the systemic circulation it must penetrate the "mucus barrier". An understanding of the characteristics of the mucus barrier is therefore important in the design of mucus penetrating drug delivery vehicles e.g. nanoparticles. Here, a range of nanoparticles -silica, aluminium coated silica, poly (lactic-co-glycolic acid) (PLGA) and PEGylated PLGA -each with known but different physicochemical characteristics were examined in the presence of mucin to identify those characteristics that engender nanoparticle/mucin interactions and thus, to define "design rules" for mucus penetrating (nano) particles (MPP), at least in terms of the surface characteristics of charge & hydrophilicity. Dynamic light scattering (DLS) and rheology have been used to assess the interaction between such nanoparticles and mucin. It was found that negatively charged and hydrophilic nanoparticles do not exhibit an interaction with mucin whereas positively charged and hydrophobic nanoparticles show a strong interaction. Surface grafted poly (ethylene glycol) (PEG) chains significantly reduced this interaction. This study clearly demonstrates that the established colloid science techniques of DLS and rheology are very powerful screening tools to probe nanoparticle/mucin interactions.

Hybrid Lipid/Polymer Nanoparticles for Pulmonary Delivery of siRNA: Development and Fate Upon In Vitro Deposition on the Human Epithelial Airway Barrier

“…The combined particle size distribution for the various replicates shows no change in the position and intensity of the peak. In line with previous studies, (9) the apparent dimension of bare PLGA is significantly shifted to larger sizes upon addition of mucin, reflecting strong mucin/NP hydrophobic interactions, which likely provide a basis for mucoadhesive NPs ( Supplementary Fig. S1A; Supplementary Data are available online at www.liebertpub.com/jamp).…”

“…The interactions of hNPs with mucin were further investigated by DLS as previously reported. (9) Briefly, the hNP dispersions in mucin were examined with the Malvern Zetasizer Nano ZS (Malvern Instruments, United Kingdom). Experiments were run in triplicate and results are reported as representative size distribution by intensity of hNPs in mucin versus hNPs in water.…”

“…(6,7) Nevertheless, particle engineering with excipients aimed to overcome the mucus-lined human lung epithelial barrier is essential. (8,9) In the attempt to combine the most valuable properties of both lipid and polymeric nanocarriers, hybrid lipid-polymer NPs (hNPs) have recently been proposed. (10,11) Thanks to their ability to form a shell upon the polymer core, lipids may be useful to impart peculiar surface properties to the carrier, likely tuning NP interactions with the lung environment, while enhancing their tolerance in the pulmonary tract.…”

Physicochemical properties of mucus and their impact on transmucosal drug delivery

“…For a nanoparticle to traverse mucus, it must possess desired surface characteristics to avoid adhesion and steric inhibition by the mucin fiber mesh. It has been demonstrated that poly(lactic-co-glycolic acid) (PLGA) and polystyrene particles functionalized with mucus inert polymers such as poly(ethylene glycol) (PEG) enhanced mucus transport in pig gastric mucus (Dawson et al, 2004; Griffiths et al, 2015), pig intestinal mucus (Abdulkarim et al, 2015; Groo et al, 2014), mouse vaginal mucus (Ensign et al, 2012b), human cervicovaginal mucus (Lai et al, 2007; Mert et al, 2012; Tang et al, 2009a; Xu et al, 2013a; Xu et al, 2015), human respiratory mucus (Schuster et al, 2013), cystic fibrosis (CF) sputum (Suk et al, 2011; Suk et al, 2009; Tang et al, 2009a), and bovine vitreous ex vivo (Xu et al, 2013b). Moreover, our group has previously demonstrated that carboxyl and amine-functionalized nanoparticles disrupt the mucus barrier and improve drug permeation up to 4.9-fold with 200 nm carboxyl-nanoparticles in porcine gastric mucus compared controls without particles (McGill and Smyth, 2010).…”

Mucus models to evaluate the diffusion of drugs and particles

“…Isothermal titration calorimetry (ITC), a technique which measures the heat released or absorbed during a biomolecular binding event[88], revealed that binding of PLGA-PEG nanoparticles (~100 nm) with Sigma bovine submaxillary gland mucin decreased as a function of conjugated PEG concentration (0–25 wt% PEG). Dynamic light scattering was also used to determine interactions between Sigma gastric mucin and negatively- or positively-charged silica nanoparticles (10–15 nm diameter)[89]. Solutions containing nanoparticle only, mucin only, and nanoparticle mixed with mucin were analyzed at 37 °C with a scattering angle of 173 degrees.…”