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Nanoparticle accumulation and transcytosis in brain endothelial cell layers
2013-09, Ye, Dong, Nic Raghnaill, Michelle, Bramini, Mattia, Mahon, Eugene, Åberg, Christoffer, Salvati, Anna, Dawson, Kenneth A.
The blood–brain barrier (BBB) is a selective barrier, which controls and limits access to the central nervous system (CNS). The selectivity of the BBB relies on specialized characteristics of the endothelial cells that line the microvasculature, including the expression of intercellular tight junctions, which limit paracellular permeability. Several reports suggest that nanoparticles have a unique capacity to cross the BBB. However, direct evidence of nanoparticle transcytosis is difficult to obtain, and we found that typical transport studies present several limitations when applied to nanoparticles. In order to investigate the capacity of nanoparticles to access and transport across the BBB, several different nanomaterials, including silica, titania and albumin- or transferrin-conjugated gold nanoparticles of different sizes, were exposed to a human in vitro BBB model of endothelial hCMEC/D3 cells. Extensive transmission electron microscopy imaging was applied in order to describe nanoparticle endocytosis and typical intracellular localisation, as well as to look for evidence of eventual transcytosis. Our results show that all of the nanoparticles were internalised, to different extents, by the BBB model and accumulated along the endo–lysosomal pathway. Rare events suggestive of nanoparticle transcytosis were also observed for several of the tested materials.
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Transferrin-functionalized nanoparticles lose their targeting capabilities when a biomolecule corona adsorbs on the surface
2013-01-20, Salvati, Anna, Pitek, Andrzej S., Monopoli, Marco P., Prapainop, Kanlaya, Baldelli Bombelli, Francesca, Hristov, Delyan R., Kelly, Philip, Åberg, Christoffer, Mahon, Eugene, Dawson, Kenneth A.
Nanoparticles have been proposed as carriers for drugs, genes and therapies to treat various diseases1, 2. Many strategies have been developed to target nanomaterials to specific or over-expressed receptors in diseased cells, and these typically involve functionalizing the surface of nanoparticles with proteins, antibodies or other biomolecules. Here, we show that the targeting ability of such functionalized nanoparticles may disappear when they are placed in a biological environment. Using transferrin-conjugated nanoparticles, we found that proteins in the media can shield transferrin from binding to both its targeted receptors on cells and soluble transferrin receptors. Although nanoparticles continue to enter cells, the targeting specificity of transferrin is lost. Our results suggest that when nanoparticles are placed in a complex biological environment, interaction with other proteins in the medium and the formation of a protein corona3, 4 can ‘screen’ the targeting molecules on the surface of nanoparticles and cause loss of specificity in targeting.