Gold nanoparticles (AuNPs) constitute a versatile platform supporting a wide array of therapeutic applications in nanomedicine. AuNPs are typically synthesized with core diameters ranging from 1 to 100 nm. Within this range, a subclass of ultrasmall nanoparticles can be approximately defined as those being less than 3 nm in diameter. Recently, several studies have argued that AuNPs in this ultrasmall size regime can present distinct advantages for use in vivo. In particular, ultrasmall AuNPs coated with the natural tripeptide glutathione (GSH) have emerged as an important nanoparticle system, since they have been found to display favorable physiological properties such as renal clearance and tumor accumulation, thus holding promise for use in vivo. Clearly, the continued development of ultrasmall GSHcoated AuNPs (AuGSH) for potential applications in vivo should greatly benefit from a more fundamental understanding of the particles biointeractions. For example, the favorable bio-responses observed for AuGSH in vivo may be somewhat surprising considering the nanoparticles are negatively charged. Indeed, compared to zwitterionic or PEGylated nanoparticles, charged AuNPs are much more prone to nonspecific binding with serum proteins and aggregation in high ionic strength biological fluid. We have probed the biointeractions of ultrasmall AuGSH in vitro, focusing on their ability to resist aggregation and binding from serum proteins. First, we prepared 2 nm diameter AuGSH nanoparticles by producing molecularly defined Au144(p-mercaptobenzoic acid)60 particles (AuMBA) followed by ligand exchange with GSH. We then investigated ultrasmall AuGSH alongside AuMBA, pointing out these particles have shown contrasting behavior in vivo, since the latter are not renal clearable and accumulate in the liver and spleen. In parallel, we have also synthesized differently sized ultrasmall AuGSH nanoparticles (1.4 and 2.5 nm in core diameter) to underscore the effect of small size variations on their biointeractions. Finally, we perform computer simulations to gain atomic-level insight into the effect of size and solution composition on interparticle interactions. Despite having net negative charge, our results showed that 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, we found 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.
| Sousa, Alioscka A; Hassan, Sergio A; Knittel, Luiza L et al. (2016) Biointeractions of ultrasmall glutathione-coated gold nanoparticles: effect of small size variations. Nanoscale 8:6577-88 |
| Sousa, Alioscka A; Morgan, Jeffrey T; Brown, Patrick H et al. (2012) Synthesis, characterization, and direct intracellular imaging of ultrasmall and uniform glutathione-coated gold nanoparticles. Small 8:2277-86 |
| Venzo, Alfonso; Antonello, Sabrina; Gascon, Jose A et al. (2011) Effect of the charge state (z = -1, 0, +1) on the nuclear magnetic resonance of monodisperse Au25[S(CH2)2Ph]18(z) clusters. Anal Chem 83:6355-62 |
