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Review
. 2012:7:5577-91.
doi: 10.2147/IJN.S36111. Epub 2012 Nov 2.

The role of surface charge in cellular uptake and cytotoxicity of medical nanoparticles

Eleonore Fröhlich  1
Affiliations
Review

The role of surface charge in cellular uptake and cytotoxicity of medical nanoparticles

Eleonore Fröhlich. Int J Nanomedicine. 2012.

Abstract

Many types of nanoparticles (NPs) are tested for use in medical products, particularly in imaging and gene and drug delivery. For these applications, cellular uptake is usually a prerequisite and is governed in addition to size by surface characteristics such as hydrophobicity and charge. Although positive charge appears to improve the efficacy of imaging, gene transfer, and drug delivery, a higher cytotoxicity of such constructs has been reported. This review summarizes findings on the role of surface charge on cytotoxicity in general, action on specific cellular targets, modes of toxic action, cellular uptake, and intracellular localization of NPs. Effects of serum and intercell type differences are addressed. Cationic NPs cause more pronounced disruption of plasma-membrane integrity, stronger mitochondrial and lysosomal damage, and a higher number of autophagosomes than anionic NPs. In general, nonphagocytic cells ingest cationic NPs to a higher extent, but charge density and hydrophobicity are equally important; phagocytic cells preferentially take up anionic NPs. Cells do not use different uptake routes for cationic and anionic NPs, but high uptake rates are usually linked to greater biological effects. The different uptake preferences of phagocytic and nonphagocytic cells for cationic and anionic NPs may influence the efficacy and selectivity of NPs for drug delivery and imaging.

Keywords: dendrimers; endocytosis; lysosomes; plasma membrane; polystyrene particles; quantum dots.

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Figures

Figure 1
Figure 1
Targets for cytotoxicity of nanoparticles (NPs). Notes: NPs may act through extracellular generation of reactive oxygen species (ROS) (1), they may physically damage the plasma membrane by causing holes (2) or bind to membrane proteins like nicotinamide adenine dinucleotide phosphate-oxidase (3), Ca2+ channels (4), and membrane receptors (5), thereby inducing oxidative signaling, increasing intracellular Ca2+ levels and activating second-messenger cascades. Inside the cells, NPs may interfere with mitochondrial metabolism (6), causing generation of radicals and induction of apoptosis. Intracellular ROS generation by NPs or by metals from lysosomal degradation (7) as well as lysosomal disruption (8) and direct binding to components of the cytoskeleton (9) and the induction of structural alterations of proteins (10) are additional modes of toxic actions. In the nucleus, interference with the transcription machinery and oxidative damage of the DNA (11) may occur.
Figure 2
Figure 2
Simplified representation of active uptake mechanisms in nonphagocytic cells. Notes: Nanoparticle (●) uptake has been evaluated mainly according to macropinocytosis, represented here as only one route, through macropinosome (MP), clathrin-mediated uptake by clathrin-coated pits (CC), and caveolae-dependent uptake by caveosomes (Cav). Uptake by clathrin-independent caveolae-independent endocytosis, which includes flotillin-, Arf6-, Cdc42-, and RhoA-dependent uptake, is also presented as only one route. Fluid-phase endocytosis, which mainly uses the clathrin-coated pits, is not depicted as a separate route. All pathways deliver their content to endosomes (E), late endosomes (LE) and lysosomes (L); the content of caveolosomes may also be delivered to the endoplasmic reticulum (ER) and the Golgi apparatus. Vesicular transport through the cell occurs through transcytotic vesicles (TV). © 2012, Elsevier. Reproduced with permission from Fröhlich E, Roblegg E. Models for oral uptake of nanoparticles in consumer products. Toxicology. 2012;291(1–3):8.
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