(526e) Mucus-Penetrating Nanoparticles for Transmucosal Drug/Gene Delivery

Viscoelastic human mucus gels protect the lungs, GI tract, reproductive tract, eye and more from infectious pathogens and foreign particulates. The human mucus barrier was recently reported as impermeable to polymer nanoparticles as small as 59 nm. Particles that cannot move through the outer layers of mucus are cleared from the mucosal tissue within seconds to at most a few hours. This reality has strongly limited development of long-lasting controlled release systems to mucus-covered tissues, and likely has played a major role in thwarting gene therapy of mucosal tissues as well, especially in cystic fibrosis.

We hypothesized that adhesion to mucus was a critical rate-limiting barrier to nanoparticle transport through mucus layers. We sought to mimic the hydrophilic and net-neutral surface properties of viruses capable of rapidly moving through human mucus. Our initial search for a candidate material that could endow these surface properties on synthetic particles led us to poly(ethylene-glycol), or PEG. Paradoxically, PEG had a considerable history of use as a muco-adhesive.

This talk will describe our recent discovery that coating synthetic nanoparticles with high densities of low molecular weight PEG allows particles with sizes of at least 500 nm in diameter to rapidly transport through undiluted human mucus nearly as fast as they move through pure water. In contrast, high molecular weight PEG coating makes them even more adhesive to mucus than without coatings. We show that PEG density is especially critical as particle size diminishes from 500- to 100-nm. We also discovered that the spacings (pores) within the human mucus mesh are much larger than previously appreciated, which provides a significant opportunity for controlled drug delivery using large nanoparticles. We will describe the development of next generation mucus-penetrating particles, composed entirely of GRAS materials, that offers sustained drug release over days. We will also discuss the development of particles that rapidly penetrate the highly viscoelastic sputum expectorated from cystic fibrosis patients as well as sinus mucus collected from chronic rhinosinusitis patients.