Lipid nanovehicles with adjustable surface properties for overcoming multiple barriers simultaneously in oral administration.

Lipid nanoparticles (LNs) are widely investigated for oral drug delivery, and for achieving significant advantages in colloidal stability, biocompatibility and scaled-up possibility. However, researchers face challenge of developing methods to improve the ability of LNs in overcoming multiple barriers (i.e., mucus and epithelium barrier) in gastrointestinal (GI) tract because of the contradictory requirement of nanoparticle (NP) surface properties in the two processes. Therefore, we designed novel LNs with adjustable surface properties by coating lipid core with hydrophobic substitutes grafting N-(2-hydroxypropyl) methacrylamide copolymer (pHPMA). In the present study, different substitutes (i.e., monocyclic, polycyclic, and linear segments) were grafted on pHPMA backbone. Screening studies demonstrated that type and grafting degree of substitutes both influenced hydrophilic-hydrophobic properties of NP surface and improved penetration through mucus. When a hydrophilic-hydrophobic balance was achieved, NPs showed elevated mucus permeability compared with bare LNs; this phenomenon subsequently contributed to higher cellular uptake. Moreover, β-sitosterol (SITO)-modified pHPMA-coated (grafting degree: 5%) LNs (5% SITO-LNs) exhibited the highest mucus permeability, transepithelial transport, and in situ absorption. Interestingly, even with the highest surface hydrophilicity, 5% SITO-LNs with Caco-2 cells did not show impaired membrane affinity, which was not observed in other groups. Further investigations of mechanism demonstrated that membrane affinity was significantly enhanced by β-SITO-mediated interaction with Niemann-Pick C1-like 1 (NPC1L1) protein on cell membranes. These results proved that hydrophobic substitutes play a critical role in altering hydrophilic-hydrophobic property of particle surface and improving penetration through multiple barriers. β-SITO-induced specific interaction can provide additional benefits to efficiency of oral delivery of LNs.