TY - JOUR
T1 - Transport mechanism of doxorubicin loaded chitosan based nanogels across intestinal epithelium
AU - Feng, Chao
AU - Sun, Guohui
AU - Wang, Zhiguo
AU - Cheng, Xiaojie
AU - Park, Hyunjin
AU - Cha, Dongsu
AU - Kong, Ming
AU - Chen, Xiguang
N1 - Funding Information:
This work was supported by National Natural Science Foundation of China (Nos. 81271727, 31240007), International Science Technology Cooperation Program of China (No. 2013DFG32880), Ph.D. Programs Foundation of Ministry of Education of China (No. 20120132110012) and Scholarship Award for Excellent Doctoral Student granted by Ministry of Education.
PY - 2014/5
Y1 - 2014/5
N2 - 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 Ca2+ 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 Ca2+, which confirmed that the higher capacity to binding Ca2+ of CS/CMCS-NGs was beneficial for transport of DOX.
AB - 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 Ca2+ 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 Ca2+, which confirmed that the higher capacity to binding Ca2+ of CS/CMCS-NGs was beneficial for transport of DOX.
KW - Carboxymethyl chitosan
KW - Doxorubicin hydrochloride
KW - Drug permeability
KW - Nanogels
KW - Oral delivery
KW - Transport pathway
UR - http://www.scopus.com/inward/record.url?scp=84901622051&partnerID=8YFLogxK
U2 - 10.1016/j.ejpb.2013.11.007
DO - 10.1016/j.ejpb.2013.11.007
M3 - Article
C2 - 24316340
AN - SCOPUS:84901622051
SN - 0939-6411
VL - 87
SP - 197
EP - 207
JO - European Journal of Pharmaceutics and Biopharmaceutics
JF - European Journal of Pharmaceutics and Biopharmaceutics
IS - 1
ER -