Active-targeting nanocarriers can significantly improve the transcytosis of poorly water-soluble or bio-macromolecular drugs across biological barrier. However, reasons for the improvement are not understood enough, which hampered the reasonable design of active targeting nanocarriers. To illustrate how different factors influence the transport of active-targeting nanocarriers, we established ligand-decorated micelles targeting different receptors to study how the decorations influence the transcytosis of the micelles by comparing the endocytosis, transport pathway and exocytosis process.

Three different kinds of receptors, Neonatal Fc receptor (FcRn), transferrin receptor (TfR) and αvβ3 integrin were selected. They presented three different transport pathways, mainly mediating transcytosis, recycling pathway and cell binding, respectively. Their corresponding ligand FcBP, 7pep and c(RGDfK) decorated micelles with different ligand densities were prepared first. Then the effects of receptor and ligand density on the transcytosis across biological barrier were investigated.

The results showed that the uptake rate of active micelles was higher than passive micelles and an optimum ligand density with most endocytosis appeared in all functional micelles. Transport pathway study showed 7pep decorated micelles were transferred into apical recycling endosome (ARE) and exocytosed to apical plasma membrane in a ligand depended way. c(RGDfK) decorated micelles were transferred through common recycling endosome (CRE) and Golgi complex to basolateral plasma membrane instead of ARE. While FcBP decorated micelles took both the recycling pathway and transcytosis through CRE, but not Golgi complex. Proper ligand density, not the higher the better, led the most uptake. Also the apical to basolateral transcytosis ratio may not be in accordance with the uptake. Among all the itineraries, transcytosis through CRE is the best itinerary for transcytosis. So, in the design of active targeting nanocarriers to overcome biological barrier, receptor character should be considered priorly, and then ligand density should be optimized.