Functional lipid polymeric nanoparticles for oral drug delivery: Rapid mucus penetration and improved cell entry and cellular transport

To improve Biopharmaceutics Classification System class IV drug bioavailability, mucus and underlying intestinal epithelial barriers must be overcome. Hydrophilic nanoparticle coatings may hinder cellular uptake and transport. We integrated hydrophilic, detachable poly(N-(2-hydroxypropyl) methacrylamide) with vitamin B12-modified chitosan into lipid polymeric nanoparticles (H/VC-LPNs) to enhance mucus penetration, intracellular uptake, and transepithelial absorption. Multiple particle tracking revealed accelerated mucus diffusion into porcine mucus in vitro. The nanoparticles increased uptake and intracellular distribution in Caco-2 cells, which may involve intrinsic factor receptor-mediated endocytosis and intercellular tight junctions. Integration of improved mucus penetration and intracellular absorption was confirmed by in vitro internalization kinetics in HT29-MTX/Caco-2 co-cultures and in vivo distribution, transport, and mouse Peyer's patch absorption. H/VC-LPNs substantially increased curcumin bioavailability in rats. A nanocarrier with a dissociable shell, receptor-mediated intracellular penetration, and paracellular transport may be promising for oral curcumin delivery. This study identified the key factors involved in oral bioavailability enhancement. The hydrophilic copolymer pHPMA associated with vitamin B12-modified chitosan-covered lipid polymeric nanoparticles (H/VC-LPNs) releases the pHPMA during mucus penetration. Endocytosis then occurs via the VB12 receptor along with caveolae and the caveolate-mediated route. The nanoparticles promote transepithelial absorption via paracellular transport and open tight junctions between intestinal cells. They also enter M-cells in Peyer's patches, thereby creating an alternate absorption route for drug delivery. Rapid mucus permeation, enhanced cellular uptake, and transepithelial absorption improved the oral absorption and bioavailability of curcumin. [Display omitted]