l -Carnitine conjugated chitosan-stearic acid polymeric micelles for improving the oral bioavailability of paclitaxel

Abstract

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 lg/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.

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“…Chitosan, a promising natural polysaccharide and the derivative of chitin, is used as a friendly biomaterial in tissue engineering because of its biocompatibility and easy degradation without toxicity ( 10 , 11 ). Chitosan polymeric micelles have been developed for improving the bioavailability of paclitaxel and reducing its toxicity ( 12 – 14 ). However, chitosan has various disadvantages, such as weak mechanical strength ( 15 , 16 ) and fast degradation ( 17 ).…”

Micellar Drug Delivery Systems Based on Natural Biopolymers

“…It have been demonstrated that this formulation increased the oral bioavailability of PTX for transcytosis across entorecytes. Another very recent study concerning the improvement of the oral bioavailability of PTX was carried out by Yang et al [ 54 ]. The micellar DDS is based on L-carnitine (LC) conjugated CS–SA polymeric micelles, which were prepared by solvent evaporation–hydration method.…”

Transporter-Targeted Nano-Sized Vehicles for Enhanced and Site-Specific Drug Delivery

“…This phenomenon was also observed by Xie et al [ 41 ]. L-Carnitine-conjugated micelles have also been developed to enhance the oral absorption of multiple water-insoluble drugs [ 42 , 43 ]. L-Carnitine is also a substrate for OCTN1, which is expressed in enterocytes along with OCTN2, but the affinity of OCTN1 towards L-carnitine is much lower than that of OCTN2.…”