Peptide-Functionalized Nanoparticles for the Targeted Delivery of Cytotoxins to MMP-14-Expressing Cancer Cells

As 90% of cancer-patient deaths are due to metastasis, novel therapeutics that selectively target and kill metastatic cells are desperately needed. Matrix metalloproteinase-14 (MMP-14), which plays a critical role in digesting the basement membrane and in inducing cancer cell migration, has been found to be expressed at the cell surface of circulating and metastasized tumor cells in various human cancers. We have recently shown that the IVS4 peptide, which mimics the minimal binding motif of the hemopexin-like (PEX) domain of MMP-14, interrupts MMP-14 dimerization and decreases MMP-14-mediated cell invasion. In this study, cancer-homing nanocarriers were assembled by linking IVS4 to polysaccharide-based nanoparticles (NPs), followed by the encapsulation of a pharmaceutical agent. IVS4-NPs efficiently prevented MMP-14-mediated cell migration and conferred an uptake advantage compared to the control peptide in an MMP-14-dependent manner. While the IVS4-NPs alone were not cytotoxic, drug-encapsulated NPs were shown to effectively target MMP- 14-expressing cancer cells. This novel nanotherapeutic is capable of inhibiting MMP-14-mediated functions and efficiently killing MMP-14-expressing cancer cells, without affecting the viability of non-cancer cells.