Detecting Cryptic Epitopes Created by Nanoparticles

Lynch, Iseult; Dawson, Kenneth A.; Linse, Sara

doi:10.1126/stke.3272006pe14

Cited by 243 publications

(220 citation statements)

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“…These particles are small enough to enter almost all areas of the body, including cells and organelles, leading potentially to a new approach to medicine (NanoMedicine) or even a source of biological hazard (1)(2)(3)(4). Despite the remarkable speed of development of nanoscience, relatively little is known about the interaction of nanoscale objects with biological systems, and this is now a serious bottleneck in the whole nanomedicine and nanotoxicology enterprise.…”

mentioning

confidence: 99%

Understanding the nanoparticle–protein corona using methods to quantify exchange rates and affinities of proteins for nanoparticles

Cedervall¹,

Lynch²,

Lindman

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Due to their small size, nanoparticles have distinct properties compared with the bulk form of the same materials. These properties are rapidly revolutionizing many areas of medicine and technology. Despite the remarkable speed of development of nanoscience, relatively little is known about the interaction of nanoscale objects with living systems. In a biological fluid, proteins associate with nanoparticles, and the amount and presentation of the proteins on the surface of the particles leads to an in vivo response. Proteins compete for the nanoparticle ''surface,'' leading to a protein ''corona'' that largely defines the biological identity of the particle. Thus, knowledge of rates, affinities, and stoichiometries of protein association with, and dissociation from, nanoparticles is important for understanding the nature of the particle surface seen by the functional machinery of cells. Here we develop approaches to study these parameters and apply them to plasma and simple model systems, albumin and fibrinogen. A series of copolymer nanoparticles are used with variation of size and composition (hydrophobicity). We show that isothermal titration calorimetry is suitable for studying the affinity and stoichiometry of protein binding to nanoparticles. We determine the rates of protein association and dissociation using surface plasmon resonance technology with nanoparticles that are thiol-linked to gold, and through size exclusion chromatography of protein-nanoparticle mixtures. This method is less perturbing than centrifugation, and is developed into a systematic methodology to isolate nanoparticle-associated proteins. The kinetic and equilibrium binding properties depend on protein identity as well as particle surface characteristics and size.

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confidence: 99%

Understanding the nanoparticle–protein corona using methods to quantify exchange rates and affinities of proteins for nanoparticles

Cedervall¹,

Lynch²,

Lindman

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

2,802

2,561

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“…Nanomedicine and nanodiagnostics are believed to offer hope with some of the most intractable challenges in human health (1). However, relatively little is known about the potential biological risks from nanoparticles, and growing awareness of these issues has led to the emergence of the field of nanotoxicology (2)(3)(4). There is little evidence as yet to imply that nanoscale objects introduce the potential for disease, apart from the long-known induction of the aggressive cancer mesothelioma by nanorods of blue asbestos (5).…”

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confidence: 99%

“…Nanoparticles are almost invariably coated with proteins when they enter a biological fluid (11)(12)(13)(14), with consequent structural and functional perturbations of the surface-bound state of the protein (3). Proteins may be bound in a native-like or denatured form depending on protein surface charge, hydrophobicity, and intrinsic stability, but also depending on particle characteristics (15,16).…”

mentioning

confidence: 99%

Nucleation of protein fibrillation by nanoparticles

Linse

Cabaleiro-Lago

Xue

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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810

769

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Nanoparticles present enormous surface areas and are found to enhance the rate of protein fibrillation by decreasing the lag time for nucleation. Protein fibrillation is involved in many human diseases, including Alzheimer's, Creutzfeld-Jacob disease, and dialysis-related amyloidosis. Fibril formation occurs by nucleationdependent kinetics, wherein formation of a critical nucleus is the key rate-determining step, after which fibrillation proceeds rapidly. We show that nanoparticles (copolymer particles, cerium oxide particles, quantum dots, and carbon nanotubes) enhance the probability of appearance of a critical nucleus for nucleation of protein fibrils from human ␤2-microglobulin. The observed shorter lag (nucleation) phase depends on the amount and nature of particle surface. There is an exchange of protein between solution and nanoparticle surface, and ␤2-microglobulin forms multiple layers on the particle surface, providing a locally increased protein concentration promoting oligomer formation. This and the shortened lag phase suggest a mechanism involving surface-assisted nucleation that may increase the risk for toxic cluster and amyloid formation. It also opens the door to new routes for the controlled self-assembly of proteins and peptides into novel nanomaterials.amyloid ͉ nanotoxicology ͉ surface-assisted nucleation

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“…A significant step in this area has been taken by Cedervall et al (9) in this issue of PNAS on development of methods for probing the association of proteins to nanoparticles: Such association is almost always a first step when nanoparticles enter a biological fluid, so that when we think of the interactions of nanoparticles with a living system, we are really speaking of protein-coated particles. Adsorption of the proteins onto the particle surface can lead to altered conformation, exposure of novel ''cryptic'' peptide epitopes, perturbed function (caused by structural effects or local high concentration), or avidity effects arising from the close spatial repetition of the same protein (10). Thus, although protein adsorption has been studied classically both on planar surfaces and in colloidal dispersions (11)(12)(13), the focus by Cedervall et al on the specific binding rates and affinities of different plasma-related proteins to nanoparticles is a welcome development in this field.…”

mentioning

confidence: 99%