Unveiling the Potential of Surface Polymerized Drug Nanocrystals in Targeted Delivery

Abstract

Nanocrystals (NCs) have entirely changed the panorama ofhydrophobic drug delivery, showing improved biopharmaceutical performancethrough multiple administration routes. NCs are potential highly loaded nanovectorsdue to their pure drug composition, standing out from conventional polymers andlipid nanoparticles that have limited drug-loading capacity. However, research in thisarea is limited. This study introduces the concept of surface modification of drugNCs through single-layer poly(ethylene glycol) (PEG) polymerization as aninnovative strategy to boost targeting efficiency. The postpolymerization analysisrevealed size and composition alterations, indicating successful surface engineeringof NCs of the model drug curcumin of approximately 200 nm. Interestingly, mucosaltissue penetration analysis showed enhanced entry for fully coated and low crosslinked(LCS) PEG NCs, with an increase of 15 μg/cm2 compared to the controlNCs. In addition, we found that polymer chemistry variations on the NCs’ surfacenotably impacted mucin binding, with those armored with LCS PEG showing the most significant reduction in interaction with thisglycoprotein. We validated this strategy in an in vitro nose-to-brain model, with all of the NCs exhibiting a promising ability to crossa tight monolayer. Furthermore, the metabolic and pro-inflammatory activity revealed clear indications that, despite surfacemodifications, the efficacy of curcumin remains unaffected. These findings highlight the potential of surface PEGylated NCs intargeted drug delivery. Altogether, this work sets the baseline for further exploration and optimization of surface polymerized NCsfor enhanced drug delivery applications, promising more efficient treatments for specific disorders and conditions requiring activetargeting.