title: Enhancing the intestinal absorption of low molecular weight chondroitin sulfate by conjugation with α-linolenic acid and the transport mechanism of the conjugates.
abstract: 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 (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, 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.
authors: Key Laboratory of Chemical Biology of Natural Products (Ministry of Education), Institute of Biochemical and Biotechnological Drugs, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China; College of Pharmaceutical Sciences, Taishan Medical University, Taian 271000, China.
authors: Yuliang
authors: Y
authors: Xiao
authors: Key Laboratory of Chemical Biology of Natural Products (Ministry of Education), Institute of Biochemical and Biotechnological Drugs, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors: Pingli
authors: P
authors: Li
authors: Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors: Yanna
authors: Y
authors: Cheng
authors: Key Laboratory of Chemical Biology of Natural Products (Ministry of Education), Institute of Biochemical and Biotechnological Drugs, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors: Xinke
authors: X
authors: Zhang
authors: Key Laboratory of Chemical Biology of Natural Products (Ministry of Education), Institute of Biochemical and Biotechnological Drugs, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors: Juzheng
authors: J
authors: Sheng
authors: College of Pharmaceutical Sciences, Taishan Medical University, Taian 271000, China.
authors: Decai
authors: D
authors: Wang
authors: Key Laboratory of Chemical Biology of Natural Products (Ministry of Education), Institute of Biochemical and Biotechnological Drugs, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors: Juan
authors: J
authors: Li
authors: Key Laboratory of Chemical Biology of Natural Products (Ministry of Education), Institute of Biochemical and Biotechnological Drugs, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors: Qian
authors: Q
authors: Zhang
authors: Key Laboratory of Chemical Biology of Natural Products (Ministry of Education), Institute of Biochemical and Biotechnological Drugs, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors: Chuanqing
authors: C
authors: Zhong
authors: Key Laboratory of Chemical Biology of Natural Products (Ministry of Education), Institute of Biochemical and Biotechnological Drugs, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors: Rui
authors: R
authors: Cao
authors: Key Laboratory of Chemical Biology of Natural Products (Ministry of Education), Institute of Biochemical and Biotechnological Drugs, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China; National Glycoengineering Research Center, Shandong University, Jinan 250012, China. Electronic address: 111925wj@163.com.
authors: Fengshan
authors: F
authors: Wang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D002152:Calorimetry, Differential Scanning; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D002809:Chondroitin Sulfates / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D019073:HT29 Cells; D006207:Half-Life; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D008027:Light; D008297:Male; D008823:Micelles; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D008970:Molecular Weight; D010539:Permeability; D066244:Proton Magnetic Resonance Spectroscopy; D017207:Rats, Sprague-Dawley; D012542:Scattering, Radiation; D017550:Spectroscopy, Fourier Transform Infrared; D013678:Technology, Pharmaceutical / Q000379:methods; D013818:Thermogravimetry; D017962:alpha-Linolenic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity
chemical_list: D008823:Micelles; D017962:alpha-Linolenic Acid; D002809:Chondroitin Sulfates
keywords: Chondroitin sulfate; Oral delivery; Self-aggregates; Transport mechanism; α-Linolenic acid