Unveiling the Potential of Surface Polymerized Drug Nanocrystals in Targeted Delivery.

Nanocrystals (NCs) have entirely changed the panorama of hydrophobic drug delivery, showing improved biopharmaceutical performance through multiple administration routes. NCs are potential highly loaded nanovectors due to their pure drug composition, standing out from conventional polymers and lipid nanoparticles that have limited drug-loading capacity. However, research in this area is limited. This study introduces the concept of surface modification of drug NCs through single-layer poly(ethylene glycol) (PEG) polymerization as an innovative strategy to boost targeting efficiency. The postpolymerization analysis revealed size and composition alterations, indicating successful surface engineering of NCs of the model drug curcumin of approximately 200 nm. Interestingly, mucosal tissue penetration analysis showed enhanced entry for fully coated and low cross-linked (LCS) PEG NCs, with an increase of 15 μg/cm 2 compared to the control NCs. In addition, we found that polymer chemistry variations on the NCs' surface notably impacted mucin binding, with those armored with LCS PEG showing the most significant reduction in interaction with this glycoprotein. We validated this strategy in an in vitro nose-to-brain model, with all of the NCs exhibiting a promising ability to cross a tight monolayer. Furthermore, the metabolic and pro-inflammatory activity revealed clear indications that, despite surface modifications, the efficacy of curcumin remains unaffected. These findings highlight the potential of surface PEGylated NCs in targeted drug delivery. Altogether, this work sets the baseline for further exploration and optimization of surface polymerized NCs for enhanced drug delivery applications, promising more efficient treatments for specific disorders and conditions requiring active targeting.