title: Transport mechanism of doxorubicin loaded chitosan based nanogels across intestinal epithelium.
abstract: Chitosan/carboxymethyl chitosan nanogels (CS/CMCS-NGs) could enhance the oral bioavailability of doxorubicin hydrochloride (DOX). To identify the mechanisms that support this recent observation, different transport pathways of CS/CMCS-NGs through the small intestine were studied in this work. Transcellular mechanisms were investigated in the presence of different inhibitors of protein-mediated endocytosis. A reduction of 52.32±18% of drug transport was found when clathrin-mediated endocytosis was inhibited, which demonstrated that clathrin-mediated endocytosis played an important role in the transcellular transport of DOX:CS/CMCS-NGs. The paracellular transport results showed that CMCS in NGs could produce a transient and reversible enhancement of paracellular permeability by depriving Ca(2+) from adherens junctions, whose efficacy as an absorption enhancer was about 1.7-3.3 folds higher than CS in NGs in GI tract. Finally, in vivo experiment showed that the transport capacity of DOX:CS/CMCS-NGs was significantly inhibited by extra added Ca(2+), which confirmed that the higher capacity to binding Ca(2+) of CS/CMCS-NGs was beneficial for transport of DOX.
authors: College of Marine Life Science, Ocean University of China, Qingdao, China.
authors: Chao
authors: C
authors: Feng
authors: College of Marine Life Science, Ocean University of China, Qingdao, China.
authors: Guohui
authors: G
authors: Sun
authors: Department of Plastic Surgery, The Affiliated Hospital of Medical College Qingdao University, Qingdao, China.
authors: Zhiguo
authors: Z
authors: Wang
authors: College of Marine Life Science, Ocean University of China, Qingdao, China.
authors: Xiaojie
authors: X
authors: Cheng
authors: Graduate School Biotechnology, Korea University, Seoul, South Korea.
authors: Hyunjin
authors: H
authors: Park
authors: Graduate School Biotechnology, Korea University, Seoul, South Korea.
authors: Dongsu
authors: D
authors: Cha
authors: College of Marine Life Science, Ocean University of China, Qingdao, China. Electronic address: kongming@ouc.edu.cn.
authors: Ming
authors: M
authors: Kong
authors: College of Marine Life Science, Ocean University of China, Qingdao, China. Electronic address: xgchen@ouc.edu.cn.
authors: Xiguang
authors: X
authors: Chen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D001692:Biological Transport; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D048271:Chitosan / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004337:Drug Carriers / Q000737:chemistry*; D004705:Endocytosis; D005782:Gels; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008856:Microscopy, Fluorescence; D049329:Nanostructures / Q000737:chemistry*; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D005782:Gels; D004317:Doxorubicin; D048271:Chitosan
keywords: Carboxymethyl chitosan; Doxorubicin hydrochloride; Drug permeability; Nanogels; Oral delivery; Transport pathway