Combined Importance of Non-Specific and Specific Interactions on the Cellular Uptake Kinetics of Peptide-Functionalized Mesoporous Silica Nanoparticles Targeting Integrins In Vitro

Determination of optimum ligand densities on nanoparticles that result in the highest nanoparticle uptake by the target cells has been the focus of many recent reports. However, analysis of the parallel influence of other important parameters affecting nanoparticle uptake, for example, charge, has achieved less attention. Here, we report results related to the influence of targeting peptide surface concentration on the cellular uptake of mesoporous silica nanoparticles, MSNs, targeting αvβ3 integrins on the cell lines differing in receptor density. For each particle system, the total peptide surface concentration was kept constant, and the targeting peptide concentration was varied through variations of the ratio of the targeting peptide to scrambled peptide. Both anionic carboxylated and cationic aminated MSNs were used. Clear differences in the cellular uptake kinetics as well as the degree of active targeting were observed, which are rationalized through a combination of nanoparticle adhesion strength to the cellular membrane influenced both by the presence of targeting ligand and particle surface charge and of receptor density on the target cells. Our results highlight the important influence of non-specific nanoparticle−cell interactions on active targeting outcomes.