Covalent Grafting of Hyaluronic Acid on Drug Nanocrystals - Application in Mucosal Delivery

Nanocrystals (NCs) represent an advanced drug delivery platform due to their nearly 100% drug loading capacity, enhanced solubility, and improved tissue penetration. The surface-rich structure NCs enable chemical modifications, with covalent grafting emerging as a superior strategy to impart stability and targeted functional groups. In this study, we explore the development of curcumin nanocrystals (CUR-NCs) covalently grafted with hyaluronic acid (HA). To enhance mucosal targeting and permeation, an innovative surface functionalization strategy was employed: hyaluronic acid (HA) was chemically grafted onto the Chitosan (CS) NCs through EDC/NHS-mediated chemistry. This surface conjugation was confirmed through FTIR and ¹ H-NMR analyses, validating the successful formation of HA-CS-CUR-NCs. The resulting nanoparticles exhibited an average particle size of 110 nm, remaining within the ideal range for mucosal delivery. Importantly, cytotoxicity assays on THP1 monocytes and NIH/3T3 fibroblasts revealed that the HA-CS-CUR-NCs possessed excellent biocompatibility properties. Ex vivo mucosal deposition studies using neonatal porcine tissue demonstrated significantly improved mucopenetration with HA-functionalized NCs, achieving 37.3 ± 26% drug deposition after 24 hours, compared to only 1.81 ± 1% for non-functionalized CUR-NCs. These findings position HA-CS-CUR-NCs as a promising platform for advanced mucosal drug delivery, combining nanoscale precision with bioresponsive surface chemistry to enhance therapeutic outcomes.