Nanoparticle diffusion within intestinal mucus: Three-dimensional response analysis dissecting the impact of particle surface charge, size and heterogeneity across polyelectrolyte, pegylated and viral particles

Abstract

Multiple particle tracking (MPT) methodology was used to dissect the impact of nanoparticle surface charge and size upon particle diffusion through freshly harvested porcine jejunum mucus. The mucus was characterised rheologically and by atomic force microscopy. To vary nanoparticle surface charge we used a series of self-assembly polyelectrolyte particles composed of varying ratios of the negatively charged polyacrylic acid polymer and the positively charged chitosan polymer. This series included a neutral or near-neutral particle to correspond to highly charged but near-neutral viral particles that appear to effectively permeate mucus. In order to negate the confounding issue of self-aggregation of such neutral synthetic particles a sonication step effectively reduced particle size (to less than 340 nm) for a sufficient period to conduct the tracking experiments. Across the polyelectrolyte particles a broad and meaningful relationship was observed between particle diffusion in mucus (×1000 difference between slowest and fastest particle types), particle size (104-373 nm) and particle surface charge (-29 mV to +19.5 mV), where the beneficial characteristic promoting diffusion was a neutral or near-neutral charge. The diffusion of the neutral polyelectrolyte particle (0.02887 cm S(-1)×10(-9)) compared favourably with that of a highly diffusive PEGylated-PLGA particle (0.03182 cm(2) S(-1)×10(-9)), despite the size of the latter (54 nm diameter) accommodating a reduced steric hindrance with the mucin network. Heterogeneity of particle diffusion within a given particle type revealed the most diffusive 10% sub-population for the neutral polyelectrolyte formulation (5.809 cm(2) S(-1)×10(-9)) to be faster than that of the most diffusive 10% sub-populations obtained either for the PEGylated-PLGA particle (4.061 cm(2) S(-1)×10(-9)) or for a capsid adenovirus particle (1.922 cm(2) S(-1)×10(-9)). While this study has used a simple self-assembly polyelectrolyte system it has substantiated the pursuance of other polymer synthesis approaches (such as living free-radical polymerisation) to deliver stable, size-controlled nanoparticles possessing a uniform high density charge distribution and yielding a net neutral surface potential. Such particles will provide an additional strategy to that of PEGylated systems where the interactions of mucosally delivered nanoparticles with the mucus barrier are to be minimised.

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).…”

The particle in the spider's web: transport through biological hydrogels

“…In humans, the ECM is an obstacle to drug delivery, as its mesh prevents large nanoparticles from penetrating deep into tissue or tumors. 18–24 Mucus similarly controls the permeability of nanoparticles, 25,26 but can also limit diffusion of small molecules such as antibiotics.…”

Sputum Active Polymyxin Lipopeptides: Activity against Cystic Fibrosis Pseudomonas aeruginosa Isolates and Their Interactions with Sputum Biomolecules

“…In line with this postulate, it has been show that the increment of hydrophobicity decreases the diffusion kinetics of nanoparticles in mucus. 38 …”