Yuliang Xiao , Pingli Li , Yanna Cheng , Xinke Zhang , Juzheng Sheng , Decai Wang , Juan Li , Qian Zhang , Chuanqing Zhong , Rui Cao , Fengshan Wang

International Journal of Pharmaceutics 465 (2014) 143–158

ABSTRACT

The purpose of this report was to demonstrate the effect of amphiphilic polysaccharides-based selfassembling 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. a-Linolenic acid-low molecular weight chondroitin sulfate polymers(a-LNA–LMCS) were successfully synthesized, and characterized by FTIR, 1HNMR, TGA/DSC, TEM, laser light scattering and zeta potential. The significant oral absorption enhancement and elimination half-life (t1/2) 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 (Papp) 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, a-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 a-LNA–LMCS micelles, which further certified the capacity of a-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.