Biointeractions of ultrasmall glutathione-coated gold nanoparticles: effect of small size variations

Abstract

Recent in vivo studies have established ultrasmall (< 3 nm) gold nanoparticles coated with glutathione (AuGSH) as a promising platform for applications in nanomedicine. However, systematic in vitro investigations to gain a more fundamental understanding of the particles’ biointeractions are still lacking. Herein we examined the behavior of ultrasmall AuGSH in vitro, focusing on their ability to resist aggregation and adsorption from serum proteins. Despite having net negative charge, AuGSH particles were colloidally stable in biological media and able to resist binding from serum proteins, in agreement with the favorable bioresponses reported for AuGSH in vivo. However, our results revealed disparate behaviors depending on nanoparticle size: particles between 2 and 3 nm in core diameter were found to readily aggregate in biological media, whereas those strictly under 2 nm were exceptionally stable. Molecular dynamics simulations provided microscopic insight into interparticle interactions leading to aggregation and their sensitivity to the solution composition and particle size. These results have important implications, in that seemingly small variations in size can impact the biointeractions of ultrasmall AuGSH, and potentially of other ultrasmall nanoparticles as well.

Computational Study of the Forces Driving Aggregation of Ultrasmall Nanoparticles in Biological Fluids

“…The molecular origin of these correlations is not always immediately apparent. The observation that no single component of the system is responsible for the local equilibrium at close contact is in line with a previous study 13 of the same NPs in phosphate buffer solution (PBS) and may be a general feature of large, complex interfaces in biological fluids. This contrasts with the effect of salts on simpler molecular solutes 18 in which localization of individual ions at the solute/solute interface can induce strong stabilizing forces; this also appears to be the case for ultrasmall NPs in simpler aqueous solutions.…”

“…This result is statistically significant and in agreement with recent experimental observations of the same NPs in CC. 13 The basin of the potential of the AuNP-25 pair is broad, with a local minimum at an interparticle separation r cc ≈ 4.5 nm, similar to the shallow metastable state of the AuNP-14 pair at r cc ≈ 3.3 nm. The broad, shallow minima at close contact are observed in all the simulations and are typically located within a ~0.5 nm range around r cc (indicated by dashed lines).…”

“…This is in agreement with recent experimental results. 13 An effort was made to draw conclusions that are expected to hold beyond the limitations of the force field and the statistics of the present simulations. The molecular mechanisms identified are thus based on general trends and correlations of the potentials, which are generally consistent across simulations and common to both NP pairs.…”

“…Simulations in PBS show indeed that human serum albumin (HSA) develops a rather thick and heterogeneous ion atmosphere (not shown), which depletes the bulk from essential species that stabilize the NPs. 13 At physiological concentrations, the change in ion activity can be substantial. Simulations of the NPs in depleted PBS showed that both pairs are indeed destabilized (not shown).…”

Molecular dynamics simulations on the effect of size and shape on the interactions between negative Au18(SR)14, Au102(SR)44 and Au144(SR)60 nanoparticles in physiological saline

“…This result agrees with recent experimental data from ultrasmall glutathione-coated gold nanoparticles. [53] The minima in the PMF profiles of the three NPs studied in this work was found to decrease linearly with the size: $${\mathcal{W}}_{\mathit{min}}~1-6\times D$$ where D is the diameter of the NP in units of nm.…”