A Multifunctional Drug Delivery System Based on Switchable Peptide-Stabilized Emulsions

Abstract Emulsions are commonly used for drug delivery, yet they are usually limited to exclusively delivering either lipophilic compounds or hydrophilic compounds. This separation negates possible synergetic therapeutic roles between such compounds. Here, we introduce a novel design for a short peptide that can stabilize emulsions. Upon binding certain metal ions, the peptide acts as a molecular switch, changes conformation, and becomes amphiphilic. Spectroscopic methods, NMR, and molecular dynamics provide information on the mechanism of this complexation-triggered amphiphilicity. The stability of these unique emulsions is based on histidine-metal bonds, which break at low pH values, selectively releasing their contents at the extracellular pH of tumors. Paclitaxel-encapsulated emulsion demonstrated strong activity against HeLa cells with an IC 50 of 70 nM, possibly enhanced by the simultaneous release of Zn 2+ ions. Importantly, the emulsion was easily functionalized with various hexahistidine-tagged motifs that can supply the emulsions with many functions beyond drug delivery.