The intestine epithelium
is considered to be the most critical
obstacle for nanoparticles for oral delivery of water-insoluble and
poorly absorbed drugs. Based on the specific transporters located
on the apical membrane of the intestinal epithelium, the carnitine-conjugated
polymeric micelles targeting to the carnitine/organic cation transporter
2 (OCTN2) were developed by combining carnitine-conjugated poly(2-ethyl-2-oxazoline)-poly(d,
l-lactide) with monomethoxy poly(ethylene-glycol)-poly(d,
l-lactide). The carnitine-conjugated micelles with favorable
stability in gastrointestinal fluid were validated to remarkably increase
the cellular internalization and transcellular transport, while these
were not the cases in the presence of free carnitine. These were further
confirmed by more distribution of the micelles within epithelial cells,
on the apical and basolateral side of the epithelium in mice. Additionally,
identification of the carnitine-conjugated micelles by OCTN2 was detected
to facilitate cellular uptake of the micelles via fluorescence immunoassay. Both clathrin and caveolae/lipid rafts
pathways mediated endocytosis and transcellular transport of the carnitine-conjugated
micelles, implying the enrichment of endocytic and transcellular transport
pathway compared with that of carnitine-unconjugated micelles. Further,
the intracellular trafficking process of the carnitine-conjugated
micelles was tracked under confocal laser scanning microscopy, which
involved in intracellular compartments such as late endosomes, lysosomes,
endoplasmic reticulum, and Golgi apparatus as well. In conclusion,
the current study provided an efficient strategy to facilitate the
oral absorption of water-insoluble and poorly absorbed agents using
intestinal transporter-mediated polymeric micelles.