SYNTHESIS AND CHARACTERIZATION OF MUCOADHESIVE AND MUCOPENETRATIVE NANOCARRIERS FOR TREATING ANTERIOR OCULAR CONDITIONS

Abstract

Ocular drug delivery continues to face significant challenges due to the rapid clearance mechanisms of the eye, including blinking and tear turnover, which lead to poor drug bioavailability and therapeutic outcomes. To address these challenges, we have developed a range of advanced nanocarriers and microgels designed to enhance retention, optimize drug loading, and enable controlled release at the ocular surface. In the first approach, block copolymers of poly(lactic acid) (PLA) and poly(oligoethylene glycol methacrylate) (POEGMA) were synthesized with varying brush lengths, with polymers with shorter side chains (n=2, and n=8,9) showing mucosal penetration while those with longer side chains (n = 20 and n = 40) exhibited mucoadhesive properties in vitro. These differences were confirmed by rheological synergism, isothermal titration calorimetry, as well as mucosal permeation studies, highlighting the potential of these materials for optimizing ocular drug delivery. In the second approach, phenylboronic acid (PBA)-functionalized, dynamically crosslinked POEGMA-based microgels were developed to leverage the hydrophilicity of POEGMA and the mucoadhesive properties conferred by the PBA-mucin interactions. These microgels offer a high degree of tunability in terms of drug loading and release profiles, particularly for poorly soluble drugs such as ciprofloxacin and atropine. Ciprofloxacin-loaded microgels demonstrated sustained release over a two-week period and enabled effective disinfection of both Staphylococcus aureus and Pseudomonas aeruginosa, while atropine-loaded microgels enabled enhanced ocular bioavailability as indicated by prolonged pupil dilation in an in vivo rabbit model. Finallly, we applied asymmetric flow field-flow fractionation (AF4) to study the structural characteristics and interactions of both types of nanoparticles with mucin, a technique not previously explored in the context of mucoadhesion. AF4 provided unique insights into nanoparticle behaviour by tracking size distribution changes upon interaction with mucin, allowing for a more detailed understanding of mucoadhesive mechanisms. Taken together, these findings underscore the potential of our developed nanocarriers and microgels as versatile platforms for enhanced ocular drug delivery in terms of overcoming bioavailability limitations, improving therapeutic efficacy, and enabling controlled, sustained drug release for treating various ocular conditions.