An important feature necessary for biological stability of gold nanoparticles is resistance to ligand exchange. Here, we design and synthesize self-assembled monolayers of mixtures of small ligands on gold nanoparticles promoting high resistance to ligand exchange. We use as ligands short thiolated peptidols, e.g. H-CVVVT-ol, and ethylene glycol terminated alkane thiols (HS-C 11-EG 4). We present a straightforward method to evaluate the relative stability of each ligand shell against ligand exchange with small thiolated molecules. The results show that a ligand with a 'thin' stem, such as HS-C 11-EG 4, is an important feature to build a highly packed self-assembled monolayer and provide high resistance to ligand exchange. The greatest resistance to ligand exchange was found for the mixed ligand shells of the pentapeptidols H-CAVLT-ol or H-CAVYT-ol and the ligand HS-C 11-EG 4 at 30:70 (mole/mole). Mixtures of ligands of very different diameters, such as the peptidol H-CFFFY-ol and the ligand HS-C 11-EG 4, provide only a slightly lower stability against ligand exchange. These ligand shells are thus likely to be suitable for long-term use in biological environments. The method developed here provides a rapid screening tool to identify nanoparticles likely to be suitable for use in biological and biomedical applications.
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