Sugar-decorated cholesterol-core nanoparticles as potential targeting nanomedicines for the delivery of lipophilic drugs†

Targeted drug delivery is a precise and effective strategy in oncotherapy and can be achieved through sugar-decorated assemblies since glucose receptors are overexpressed on cancer cell membranes to compensate for their increased glucose demands. In this study, core–shell nanoparticles (NPs) were synthesized using amphiphilic macromolecules comprising hydrophobic cholesterol (Chol) segments conjugated to hydrophilic polyethylene oxide containing azide group (Chol-PEO₂₂-N₃) or substituted with the carbohydrate N-acetyl-D-glucosamine (Chol-PEO₂₂-GlcNAc) via a click chemistry reaction. These self-assemblies, which are smaller than 100 nm and suitable for cancer treatment, demonstrated efficient loading efficiency (exceeding 70%) with ursolic acid (UA), a hydrophobic drug, serving as a proof-of-concept for targeted therapy using natural compounds against non-small cell lung cancer. The incorporation of sugar molecules modified the structural characteristics of the nanocarriers, resulting in larger and presumably less dense particles. This modification influenced the UA release mechanism, leading to a faster and nearly complete release over a week, whereas approximately 60% of the encapsulated UA remained entrapped in the Chol-PEO₂₂-N₃ NPs. Enhanced cell cytotoxicity was achieved with UA-loaded NPs with in vitro cell viability assays indicating at least two-fold increase in the inhibitory effect of the drug-loaded nanocarriers. The targeted delivery was also demonstrated as UA-loaded Chol-PEO₂₂-GlcNAc NPs showed greater internalization by cancer cells than their healthy counterparts.