In situ monitoring of the structural change of microemulsions in simulated gastrointestinal conditions by SAXS and FRET

Mucus is tenacious. It sticks to most particles, preventing their penetration to the epithelial surface. Multiple low-affinity hydrophobic interactions play a major role in these adhesive interactions. Mucus gel is also shear-thinning, making it an excellent lubricant that ensures an unstirred layer of mucus remains adherent to the epithelial surface. Thus nanoparticles (NP) must diffuse readily through the unstirred adherent layer if they are to contact epithelial cells efficiently. This article reviews some of the physiological and biochemical properties that form the mucus barrier. Capsid viruses can diffuse through mucus as rapidly as through water and thereby penetrate to the epithelium even though they have to diffuse 'upstream' through mucus that is being continuously secreted. These viruses are smaller than the mucus mesh spacing, and have surfaces that do not stick to mucus. They form a useful model for developing NP for mucosal drug delivery.

Nanoparticles (NPs) have demonstrated great potential for the oral delivery of protein drugs that have very limited oral bioavailability. Orally administered NPs could be absorbed by the epithelial tissue only if they successfully permeate through the mucus that covers the epithelium. However, efficient epithelial absorption and mucus permeation require very different surface properties of a nanocarrier. We herein report self-assembled NPs for efficient oral delivery of insulin by facilitating both of these two processes. The NPs possess a nanocomplex core composed of insulin and cell penetrating peptide (CPP), and a dissociable hydrophilic coating of N-(2-hydroxypropyl) methacrylamide copolymer (pHPMA) derivatives. After systematic screening using mucus-secreting epithelial cells, NPs exhibit excellent permeation in mucus due to the "mucus-inert" pHPMA coating, as well as high epithelial absorption mediated by CPP. The investigation of NP behavior shows that the pHPMA molecules gradually dissociate from the NP surface as it permeates through mucus, and the CPP-rich core is revealed in time for subsequent transepithelial transport through the secretory endoplasmic reticulum/Golgi pathway and endocytic recycling pathway. The NPs exhibit 20-fold higher absorption than free insulin on mucus-secreting epithelium cells, and orally administered NPs generate a prominent hypoglycemic response and an increase of the serum insulin concentration in diabetic rats. Our study provides the evidence of using pHPMA as dissociable "mucus-inert" agent to enhance mucus permeation of NPs, and validates a strategy to overcome the multiple absorption barriers using NP platform with dissociable hydrophilic coating and drug-loaded CPP-rich core.

A major role of respiratory mucus is to trap inhaled particles, including pathogens and environmental particulates, to limit body exposure. Despite the tremendous health implications, how particle size and surface chemistry affect mobility in respiratory mucus from humans without lung disease is not known. We prepared polymeric nanoparticles densely coated with low molecular weight polyethylene glycol (PEG) to minimize muco-adhesion, and compared their transport to that of uncoated particles in human respiratory mucus, which we collected from the endotracheal tubes of surgical patients with no respiratory comorbidities. We found that 100 and 200 nm diameter PEG-coated particles rapidly penetrated respiratory mucus, at rates exceeding their uncoated counterparts by approximately 15- and 35-fold, respectively. In contrast, PEG-coated particles ≥500 nm in diameter were sterically immobilized by the mucus mesh. Thus, even though respiratory mucus is a viscoelastic solid at the macroscopic level (as measured using a bulk rheometer), nanoparticles that are sufficiently small and muco-inert can penetrate the mucus as if it were primarily a viscous liquid. These findings help elucidate the barrier properties of respiratory mucus and provide design criteria for therapeutic nanoparticles capable of penetrating mucus to approach the underlying airway epithelium. Copyright © 2013 Elsevier Ltd. All rights reserved.