Enhancing the intestinal absorption of low molecular weight chondroitin sulfate by conjugation with α-linolenic acid and the transport mechanism of the conjugates

The purpose of this report was to demonstrate the effect of amphiphilic polysaccharides-based self-assembling micelles on enhancing the oral absorption of low molecular weight chondroitin sulfate (LMCS) in vitro and in vivo , and identify the transepithelial transport mechanism of LMCS micelles across the intestinal barrier. α-Linolenic acid-low molecular weight chondroitin sulfate polymers(α-LNA–LMCS) were successfully synthesized, and characterized by FTIR, 1 HNMR, TGA/DSC, TEM, laser light scattering and zeta potential . The significant oral absorption enhancement and elimination half-life ( t 1/2 ) extension of LNA–LMCS2 in rats were evidenced by intragastric administration in comparison with CS and LMCS. Caco-2 transport studies demonstrated that the apparent permeability coefficient ( P app ) of LNA–LMCS2 was significantly higher than that of CS and LMCS ( p   <   0.001), and no significant effects on the overall integrity of the monolayer were observed during the transport process. In addition, α-LNA–LMCS micelles accumulated around the cell membrane and intercellular space observed by confocal laser scanning microscope (CLSM). Furthermore, evident alterations in the F-actin cytoskeleton were detected by CLSM observation following the treatment of the cell monolayers with α-LNA–LMCS micelles, which further certified the capacity of α-LNA–LMCS micelles to open the intercellular tight junctions rather than disrupt the overall integrity of the monolayer. Therefore, LNA–LMCS2 with low cytotoxicity and high bioavailability might be a promising substitute for CS in clinical use, such as treating osteoarthritis , atherosclerosis , etc.