title: Multifactorial determinants that govern nanoparticle uptake by human endothelial cells under flow.
abstract: Vascular endothelium is a potential target for therapeutic intervention in diverse pathological processes, including inflammation, atherosclerosis, and thrombosis. By virtue of their intravascular topography, endothelial cells are exposed to dynamically changing mechanical forces that are generated by blood flow. In the present study, we investigated the interactions of negatively charged 2.7 nm and 4.7 nm CdTe quantum dots and 50 nm silica particles with cultured endothelial cells under regulated shear stress (SS) conditions. Cultured cells within the engineered microfluidic channels were exposed to nanoparticles under static condition or under low, medium, and high SS rates (0.05, 0.1, and 0.5 Pa, respectively). Vascular inflammation and associated endothelial damage were simulated by treatment with tumor necrosis factor-α (TNF-α) or by compromising the cell membrane with the use of low Triton X-100 concentration. Our results demonstrate that SS is critical for nanoparticle uptake by endothelial cells. Maximal uptake was registered at the SS rate of 0.05 Pa. By contrast, endothelial exposure to mild detergents or TNF-α treatment had no significant effect on nanoparticle uptake. Atomic force microscopy demonstrated the increased formation of actin-based cytoskeletal structures, including stress fibers and membrane ruffles, which have been associated with nanoparticle endocytosis. In conclusion, the combinatorial effects of SS rates, vascular endothelial conditions, and nanoparticle physical and chemical properties must be taken into account for the successful design of nanoparticle-drug conjugates intended for parenteral delivery.
authors: Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.
authors: Stephen Paul
authors: SP
authors: Samuel
authors: Namrata
authors: N
authors: Jain
authors: Frank
authors: F
authors: O'Dowd
authors: Toby
authors: T
authors: Paul
authors: Dmitry
authors: D
authors: Kashanin
authors: Valerie A
authors: VA
authors: Gerard
authors: Yurii K
authors: YK
authors: Gun'ko
authors: Adriele
authors: A
authors: Prina-Mello
authors: Yuri
authors: Y
authors: Volkov
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D019187:Cadmium Compounds / Q000737:chemistry / Q000493:pharmacokinetics; D048708:Cell Growth Processes / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D044085:Microfluidics; D018625:Microscopy, Atomic Force; D008954:Models, Biological; D053758:Nanoparticles / Q000737:chemistry*; D017830:Octoxynol; D045663:Quantum Dots; D012822:Silicon Dioxide / Q000737:chemistry / Q000493:pharmacokinetics; D013314:Stress, Mechanical; D013691:Tellurium / Q000737:chemistry / Q000493:pharmacokinetics; D014409:Tumor Necrosis Factor-alpha
chemical_list: D019187:Cadmium Compounds; D014409:Tumor Necrosis Factor-alpha; D012822:Silicon Dioxide; D017830:Octoxynol; D013691:Tellurium; C028337:cadmium telluride