A delivery system based on l-carnitine (LC) conjugated chitosan (CS)-stearic acid polymeric micelles has been developed for improving the oral bioavailability of paclitaxel (PTX) through targeting intestinal organic cation/carnitine transporter 2 (OCTN2). Stearic acid grafted chitosan (CS-SA), as micelle skeleton material, was synthesized by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)-mediated coupling reaction. The PTX-loaded micelles were prepared by solvent evaporation-hydration method, and the ligand LC was conjugated onto the micelle surface by anchoring its derivative stearoyl group to the lipophilic core of micelle. The modified polymeric micelles showed regular spherical shapes with small particle size of 157.1 ± 5.2 nm and high drug loading capacity of 15.96 ± 0.20 wt%, and the micelle stability in water was supported by low critical micelle concentration of 14.31 ± 0.21 μg/ml. The drug-loaded micelles presented a slow and incomplete in vitro release, and the pharmacokinetic studies indicated the micelle carriers increased the relative bioavailability of PTX to 165.8% against the commercial formulation. The enhancement effect on intestinal absorption was also confirmed by the intracellular uptake of Caco-2 cells. The proposed micelle carrier system manifested a prospective tool for oral drug delivery.

Introduction: In the previous study, nanoparticles coated with trimethyl chitosan (TMC) derivatives (PPTT-NPs) could promote the oral bioavailability of panax notoginseng saponins (PNS). Herein, we chose PPTT-NPs as a model drug to study the property and mechanism of intestinal absorption in vitro and in vivo. Methods: The stability of PPTT-NPs was evaluated using simulated gastric fluid and simulated intestinal fluid. The uptake and transport of PPTT-NPs were investigated in Caco-2 and Caco-2&HT29 co-culture cells. The biosafety, intestinal permeability, adhesion, and absorption mechanism of PPTT-NPs were investigated using SD rats in vivo. The live imaging and biodistribution of PPTT-NPs were observed by IVIS. Furthermore, the effects on CYP3A4 of PPTT-NPs were investigated using testosterone as the probe substrate. Results: The results of the stability assay showed that PPTT-NPs had a strong tolerance to the pH and digestive enzymes in the gastrointestinal environment. In vitro cell experiments showed that the uptake of drugs exhibited a time-dependent. When the ratio of TMC-VB₁₂ and TMC-Cys was 1:3, the uptake capacity of PPTT-NPs was the highest. PPTT-NPs could enhance the paracellular transport of drugs by reversibly opening a tight junction. Animal experiments demonstrated that PPTT-NPs have good biological safety. PPTT-NPs had good adhesion and permeability to small intestinal mucosa. Meanwhile, PPTT-NPs needed energy and various protein to participate in the uptake of drugs. The live imaging of NPs illustrated that PPTT-NPs could prolong the residence time in the intestine. Moreover, TMC-VB₁₂ and TMC-Cys could reduce the metabolism of drugs by inhibiting CYP3A4 to a certain extent. Conclusion: The results show that TMC-VB₁₂ and TMC-Cys are effective in the transport of PPTT-NPs. PPTT-NPs can increase the intestinal adhesion of drugs and exert high permeation by intestinal enterocytes which demonstrate significant and efficient potential for oral delivery of the BCS III drugs. Graphical Abstract: