title: The transport pathways of polymer nanoparticles in MDCK epithelial cells.
abstract: Epithelial cell membranes as the typical biological barrier constitute the prime obstacle for the transport of therapeutic agents including nanomedicines. The previous studies on the interaction between nanomedicines and cells are mostly emphasized on cellular uptake and intracellular trafficking, but seldom on epithelial cells, although more and more oral nanomedicines are available now. In an attempt to clarify the transport pathways of nanomedicines in epithelial cells, the different molecular mechanisms among endocytosis, exocytosis and transcytosis processes were carefully studied and compared here using a kind of polymer nanoparticles (PNs) and MDCK epithelial cells as models. As the result, their similarity and difference were demonstrated. The similarities among all the three processes included the mediation of lipid rafts, the involvement of some protein kinases such as protein tyrosine kinase (PTK), protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K), and the existence of multiple pathways. However, the difference among these processes was very significant, including different pathways, and especially the disparate effects of lipid rafts and protein kinases for different processes. The endocytosis involved both lipid raft and clathrin mechanisms but no macropinocytosis, via the invagination of membrane but no pore formation, the exocytosis contained ER/Golgi and Golgi/PM pathways, and transcytosis included AEE/CE/BSE and Golgi/BSE pathways. The roles of lipid rafts on endocytosis were positive but that on exocytosis and transcytosis was negative. The impacts of PTK and PKC on endocytosis were positive, while the influences of PTK, PKC and P13K on AEE/CE/BSE, as well as PTK and P13K on Golgi/BSE transcytosis pathways were negative. Moreover, the discrepancy between inward and outward transport of PNs elucidated an interesting fact that the endocytosis was rather easy and outward transport including exocytosis and transcytosis was rather difficult. Finally, it was indicated by comparison with previous reports that the molecular mechanisms between PNs and macromolecules such as proteins were also dissimilar.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Bing
authors.initials: B
authors.lastname: He
authors.forename: Zengrong
authors.initials: Z
authors.lastname: Jia
authors.forename: Wenwen
authors.initials: W
authors.lastname: Du
authors.forename: Chao
authors.initials: C
authors.lastname: Yu
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Fan
authors.forename: Wenbing
authors.initials: W
authors.lastname: Dai
authors.forename: Lan
authors.initials: L
authors.lastname: Yuan
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Xueqing
authors.initials: X
authors.lastname: Wang
authors.forename: Jiancheng
authors.initials: J
authors.lastname: Wang
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D003374:Coumarins / Q000494:pharmacology; D004285:Dogs; D004705:Endocytosis / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D005089:Exocytosis / Q000187:drug effects; D005434:Flow Cytometry; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008027:Light; D061985:Madin Darby Canine Kidney Cells; D018613:Microscopy, Confocal; D008954:Models, Biological; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D015388:Organelles / Q000187:drug effects / Q000378:metabolism; D010316:Particle Size; D011108:Polymers / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D012542:Scattering, Radiation; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D003374:Coumarins; D011108:Polymers; D013844:Thiazoles; C517282:coumarin 6; D007770:L-Lactate Dehydrogenase; D011494:Protein Kinases