The Extent of Ligand–Receptor Interactions for Actively Targeted Nanoparticles as a Function of Ligand Density and Receptor Expression

The interaction between mesoporous silica nanoparticles covalently functionalized with different ratios of octreotide, a potent agonist for somatostatin receptors (SSTRs), and a scrambled peptide at a constant total peptide loading and SSTR2 was evaluated as a function of receptor expression. Both an increasing octreotide surface concentration and an increasing receptor expression level led to an increased total ligand-receptor interaction. The highest level of selectivity in terms of differences in sensor response between cells exhibiting a low and a high receptor expression level was observed at intermediate octreotide surface concentrations. However, the kinetics of particle internalization decreased with increasing receptor levels, which led to a decrease in selectivity when judged based on particle uptake as compared to the extent of ligand-receptor interactions. Our results highlight the value of direct evaluation of ligand-receptor interactions in addition to particle uptake analyses for enhancing the mechanistic understanding of nanoparticle behavior in biological systems, enabling rational design of actively targeted nanocarriers.