Functional Nanovalves on Protein-Coated Nanoparticles for In vitro and In vivo Controlled Drug Delivery

A multifunctional mesoporous drug delivery system that contains fluorescent imaging molecules, targeting proteins, and pH-sensitive nanovalves is developed and tested. Three nanovalve-mesoporous silica nanoparticle (NV-MSN) systems with varied quantities of nanovalves on the surface are synthesized. These systems are characterized and tested to optimize the trade-off between the coverage of nanovalves on the MSNs to effectively trap and deliver cargo, and the remaining underivatized silanol groups that can be used for protein attachments. The NV-MSN system that has satisfactory coverage for high loading and spare silanols is chosen, and transferrin (Tf) is integrated into the system. Abiotic studies are performed to test the operation of the nanovalve in the presence of the protein. In vitro studies are carried out to demonstrate the autonomous activation and function of the nanovalves in the system under biological conditions. Enhanced cellular uptake of the Tf-modified MSNs is seen using fluorescence microscopy and flow cytometry in MiaPaCa-2 cells. The MSNs are then tested using SCID mice, which show that both targeted and untargeted NV-MSN systems are fully functional to effectively deliver cargo. These new multifunctional nanoparticles serve proof of concept of nanovalve functionality in the presence of large proteins and demonstrate another dimension of MSN-based theranostic platforms.