Surface Modifications of Nanoparticles for Stability in Biological Fluids

Abstract

Due to the high surface: volume ratio and the extraordinary properties arising from the nanoscale (optical, electric, magnetic, etc.), nanoparticles (NPs) are excellent candidates for multiple applications. In this context, nanoscience is opening a wide range of modern technologies in biological and biomedical fields, among others. However, one of the main drawbacks that still delays its fast evolution and effectiveness is related to the behavior of nanomaterials in the presence of biological fluids. Unfortunately, biological fluids are characterized by high ionic strengths which usually induce NP aggregation. Besides this problem, the high content in biomacromolecules—such as lipids, sugars, nucleic acids and, especially, proteins—also affects NP stability and its viability for some applications due to, for example, the formation of the protein corona around the NPs. Here, we will review the most common strategies to achieve stable NPs dispersions in high ionic strength fluids and, also, antifouling strategies to avoid the protein adsorption.

Keywords: antifouling; biological fluids; colloidal stability; magnetism; nanoparticles; plasmonics; protein corona; quantum dots; surface modification.

Figure 1

Strategies to achieve stable NPs in biofluids.

Figure 2

Schematic representation of the most commonly used functional groups in surface ligands and their preferred affinity towards binding different NP materials.

Figure 3

Colloidal stability of citrate-capped (A) and pegylated Au NPs (PEG₁₀₈₀₀) (B) in solutions with high salt concentration (0.157 M NaCl). The evolution of the colloidal state was monitored over time by UV–visible spectroscopy. The pictures of the corresponding colloidal solutions are shown in the middle, corroborating the high stability of the PEG–Au NPs colloidal solution under high ionic strength conditions, compared to Au NPs–citrate that aggregate and precipitate. Reproduced from [39] with permission.

Figure 4

Schematic representation of different strategies for coating NPs with PEG. For plasmonic NPs, thiolated PEGs are by far the most widely used compounds in the pegylation process. A simple ligand exchange by adding SH-PEG when the colloids are citrate stabilized (A). If the surfactant is CTAB as for the case of Au NRs, the pegylation is conducted by successively adding surfactant Tween 20, bis(p-sulfonatophenyl) phenylphosphine dihydrate dipotassium (BSPP), HS-PEG, and NaCl into the CTAB-capped Au NRs solution, followed by its incubation at room temperature for 24 h (B). For the case of oxide particles as magnetite, the covalent attachment to the NPs surface is generally performed by oxygen bonding. In the presented example, dopamine was linked to carboxylic PEG to transfer the NPs into aqueous media and anchor PEG to their surface (C). For the case of QDs dispersed in organic phase, amines can be used for ligand exchange. In this case, octadecylamine was replaced with polyethylenimine (PEI) that was previously conjugated with PEG. In this way, PEG functionalization and the dispersion of QDs in water is achieved (D). Images reproduced from [40,41,66].with permission.

Figure 5

Schematic illustrating the influence of PEG density on surfaces serum protein adsorption to gold nanoparticles and their subsequent uptake by macrophages. The top panel shows gold nanoparticles grafted with PEG at increasing density. As PEG density increases, PEG volume decreases because of PEG−PEG steric interactions and a more compact layer is formed. The middle panel illustrates how PEG density determines the amount and relative abundance of serum proteins adsorbed to the gold nanoparticle surface after serum exposure. As the PEG density increases, fewer proteins are adsorbed. The lower panel shows that at low PEG densities, macrophage uptake is efficient and serum-dependent. At high PEG densities, macrophage uptake is driven predominantly by a less efficient serum-independent mechanism. Reproduced from [77] with permission.

Figure 6

Illustration of the protein adsorption on the surface of a NP functionalized either with zwitterionic (A) or PEG (B) ligands. Both ligands have terminal thiol groups for binding to the Au surface. The zwitterionic ligand is composed of an oligo(ethylene glycol) chain followed by a carboxybetaine group (A). Reproduced from [85,94] with permission.

Figure 7

(A) TEM image where it can be clearly seen a lipid bilayer (dioleoylphosphatidylcholine, DOPC), egg sphingomyelin (ESM), and ovine cholesterol (Chol)) on a Au NP. (B) Normalized UV–vis absorption spectra of citrate (grey) and lipid-coated (black) Au NPs. The LSPR peaks redshift from 534 nm to 538 nm after the lipid coating. (C) Formation of L-QD vesicles via solvent evaporation, hydration and probe sonication. Reproduced from [114,115] with permission.

Figure 8

Schematic illustration of BSA-, lysozyme-, trypsin-, hemoglobin-, and transferrin-functionalized QDs. Reproduced from [134] with permission.

Figure 9

Molecular structures of thiol-terminated neoglycoconjugates of N-acetylglucosamine (GlcNAc) and lactose (Lac) (A). UV−vis−NIR spectra of Au nanospheres and NRs stabilized with their corresponding glycan and original ligands (B). Hydrodynamic diameters measured in water of Au NPs stabilized with different ligands (C). TEM images of Au nanospheres and NRs stabilized with GlcNA cand Lac (D,E). Reproduced from [139] with permission.

Figure 10

Schematic representation for the synthesis of glycopeptide-grafted magnetic nanoparticles. Reproduced from [142] with permission.

Figure 11

Structure of the amphiphilic polymer poly (isobutylene-alt-maleic anhydride) (PMA), functionalized with dodecylamine. The purple box shows a monomer unit. The hydrophobic and hydrophilic parts are drawn in red and blue, respectively (A). Scheme of a Au NP transferred from chloroform to water using PMA-dodecylamine polymer (B). Incorporation of additional functionalities in the polymer around the particles linked thought an amino-terminal group to the polymer and lose look to the amino group linkage to the polymer (C). Reproduced from [63,143] with permission.

Figure 12

Schematic representation for the bioconjugation of citrate-stabilized Ag NPs with a thiolated S. aureus aptamer (A) and starch-coated magnetic NPs with amino-modified E1E2-6 aptamer (B). Reproduced from [159,163] with permission.