Stearic Acid-<i>g</i>-chitosan Polymeric Micelle for Oral Drug Delivery: In Vitro Transport and in Vivo Absorption

Stearic acid-g-chitosan (low molecular weight chitosan CS-SA) with different amino-substituted degrees was synthesized and evaluated as an oral delivery vehicle in this paper. Synthesized CS-SA with 4.47%, 24.36% and 40.36% amino-substituted degree (SD) could form micelles by self-aggregation in aqueous medium. The critical micelle concentration (CMC) ranged from about 0.16 to 0.25 mg/mL, which decreased with the increased SD of CS-SA. The CS-SA micelles had 33.4−130.9 nm size and 22.9− 48.4 mV zeta potential. CS-SA with higher SD had the smaller size and the higher zeta potential. The permeability and possible transport route of CS-SA micelles across the gastrointestinal tract was investigated by in vitro model Caco-2 cells. The results exhibited that the CS-SA micelles had good permeability, and the permeability enhanced with increasing SD of the CS-SA. The transport of the micelles showed energy, pH and concentration dependent transcytosis process, mainly through macropinocytosis and partly via fluid-phase transcytosis and caveolar route. The reversible decrease in transepithelial electrical resistance (TEER) by treatment of micelles suggested that paracellular transport pathway was another route of the micelles crossing the gastrointestinal tract. Using doxorubicin (DOX) as a model drug, the permeation results further demonstrated that the DOX transport mediated by CS-SA micelles could avoid efflux via P-glycoprotein. In vivo study demonstrated that the micelles could significantly improve the bioavailability of encapsulated drug. The results presented that the CS-SA with higher SD was a promising vehicle for oral drugs.