(705b) Production of Virus-Mimetic Mucus-Penetrating Particles for Drug and Gene Delivery In Mucosal Tissues

Therapeutic nanoparticles must rapidly penetrate human mucus to avoid clearance in the lungs, GI tract, female reproductive tract, eye, and more. For example, the gene that could cure Cystic Fibrosis (CF) has been available since 1989, but gene therapy has yet to cure a single person of CF. Efficient gene delivery through CF sputum, which possesses a bulk viscosity roughly 10,000-100,000 fold higher than water at low shear rates, has been thought to be implausible or impossible since diffusion rates of even small gene-carrier nanoparticles through such a high viscosity fluid with physiological thicknesses found in the lungs would be much too slow. The same is true for nanoparticulate drug delivery through healthy human mucus, which is ~2,000-fold more viscous than water at low shear rates.

Looking to nature for guidance, we noted that pathogens that infect mucosal surfaces have evolved net neutral and hydrophilic surfaces to minimize their adhesion to mucus. We then discovered that even large polymer nanoparticles (up to 500 nm) can rapidly penetrate human mucus through low viscosity "pores" in the human mucus gel, but only if their surfaces are rendered completely non-adhesive to mucus. A critical next step is the identification of safe coating materials that can allow a variety of promising polymer particles to penetrate human mucus.

Here, we describe a simple chemical method, adsorption of Pluronic to either hydrophobic particles or to hydrophobic adhesive regions of human mucus, that readily confers virus-mimetic muco-resistant properties to standard (mucoadhesive) particles. Pluronic is used safely in humans in many products.

Pluronic, an amphiphilic triblock polymer, contains a core polypropylene glycol segment that anchors to the adhesive core of polymeric nanoparticles, coupled with two flanking polyethylene glycol chains that present an uncharged, hydrophilic surface. Pluronic may also shield the adhesive hydrophobic patches along mucin fibers. Both particle coating with Pluronic and simple addition of Pluronic to mucus markedly improves the transport of various polymeric particles in fresh, undiluted human cervicovaginal mucus, with effective diffusivities (Deff) up to only 3-fold reduced compared to those in water. In contrast, the Deff for uncoated particles was ~4000-fold lower in mucus than in water. Much larger fractions of the uncoated particles were immobilized or otherwise hindered by mucus than the Pluronic-coated particles or uncoated particles in Pluronic-treated mucus. We show that this simple chemical method can enhance the transport of a variety of synthetic polymeric particles, offering the prospect that a wide diversity of biomaterials can be adopted for transmucosal therapeutics delivery.