title: Transport pathways of solid lipid nanoparticles across Madin-Darby canine kidney epithelial cell monolayer.
abstract: An understanding of drug delivery system transport across epithelial cell monolayer is very important for improving the absorption and bioavailability of the drug payload. The mechanisms of epithelial cell monolayer transport for various nanocarriers may differ significantly due to their variable components, surface properties, or diameter. Solid lipid nanoparticles (SLNs), conventionally formed by lipid materials, have gained increasing attention in recent years due to their excellent biocompatibility and high oral bioavailability. However, there have been few reports about the mechanisms of SLNs transport across epithelial cell monolayer. In this study, the molecular mechanisms utilized by SLNs of approximately 100 nm in diameter crossing intestinal epithelial monolayer were carefully studied using a simulative intestinal epithelial monolayer formed by Madin-Darby canine kidney (MDCK) epithelial cells. The results demonstrated that SLNs transportation did not induce a significant change on tight junction structure. We found that the endocytosis of SLNs into the epithelial cells was energy-dependent and was significantly greater than nanoparticle exocytosis. The endocytosis of SLNs was found to be rarely mediated via macropinocytosis, as confirmed by the addition of 5-(N-ethyl-N-isopropyl)amiloride (EIPA) as an inhibitory agent, and mainly depended on lipid raft/caveolae- and clathrin-mediated pathways. After SLNs was internalized into MDCK cells, lysosome was one of the main destinations for these nanoparticles. The exocytosis study indicated that the endoplasmic reticulum, Golgi complex, and microtubules played important roles in the transport of SLNs out of MDCK cells. The transcytosis study indicated that only approximately 2.5% of the total SLNs was transported from the apical side to the basolateral side. For SLNs transportation in MDCK cell monolayer, greater transport (approximately 4-fold) was observed to the apical side than to the basolateral side. Our findings may present a more comprehensive understanding on the transport of SLNs across epithelial cell monolayer.
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University , 866 Yuhangtang Road, Hangzhou 310058, People's Republic of China.
authors.forename: Gui-Hong
authors.initials: GH
authors.lastname: Chai
authors.forename: Fu-Qiang
authors.initials: FQ
authors.lastname: Hu
authors.forename: Jihong
authors.initials: J
authors.lastname: Sun
authors.forename: Yong-Zhong
authors.initials: YZ
authors.lastname: Du
authors.forename: Jian
authors.initials: J
authors.lastname: You
authors.forename: Hong
authors.initials: H
authors.lastname: Yuan
mesh_terms: D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D004285:Dogs; D004705:Endocytosis / Q000502:physiology; D005089:Exocytosis / Q000502:physiology; D061985:Madin Darby Canine Kidney Cells; D053758:Nanoparticles / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000584:Amiloride; C039614:ethylisopropylamiloride
keywords: MDCK cell monolayer; endocytosis; exocytosis; solid lipid nanoparticles; transcytosis