An experimental and theoretical approach to understand the interaction between particles and mucosal tissues

Abstract

Nanonization of poorly water-soluble drugs has shown great potential in improving their oral bioavailability by increasing drug dissolution rate and adhesion to the gastrointestinal mucus. However, the fundamental features that govern the particle-mucus interactions have not been investigated in a systematic way before. In this work, we synthesize mucin hydrogels that mimic those of freshly excised porcine mucin. By using fluorescent pure curcumin particles, we characterize the effect of particle size (200 nm, and 1.2 and 1.3 μm), concentration (18, 35, and 71 μg mL^-1), and hydrogel crosslinking density on the diffusion-driven particle penetration in vitro. Next, we derive a phenomenological model that describes the physics behind the diffusion-derived penetration and considers the contributions of the key parameters assessed in vitro. Finally, we challenge our model by assessing the oral pharmacokinetics of an anti-cancer model drug, namely dasatinib, in pristine and nanonized forms and two clinically relevant doses in rats. For a dose of 10 mg kg^-1, drug nanonization leads to a significant ∼8- and ∼21-fold increase of the drug oral bioavailability and half-life, respectively, with respect to the unprocessed drug. When the dose of the nanoparticles was increased to 15 mg kg^-1, the oral bioavailability increased though not significantly, suggesting the saturation of the mucus penetration sites, as demonstrated by the in vitro model. Our overall results reveal the potential of this approach to pave the way for the development of tools that enable a more rational design of nano-drug delivery systems for mucosal administration. STATEMENT OF SIGNIFICANCE: The development of experimental-theoretical tools to understand and predict the diffusion-driven penetration of particles into mucus is crucial not only to rationalize the design of nanomedicines for mucosal administration but also to anticipate the risks of the exposure of the body to nano-pollutants. However, a systematic study of such tools is still lacking. Here we introduce an experimental-theoretical approach to predict the diffusion-driven penetration of particles into mucus and investigate the effect of three key parameters on this interaction. Then, we challenge the model in a preliminary oral pharmacokinetics study in rats which shows a very good correlation with in vitro results. Overall, this work represents a robust platform for the modelling of the interaction of particles with mucosae under dynamic conditions.

Keywords: Mucin hydrogels; Mucosal tissues; Nanomedicine; Nanoparticles; Particle penetration mechanisms; Particle-mucus interactions.