Tumor-Cell-Surface Adherable Peptide-Drug Conjugate Prodrug Nanoparticles Inhibit Tumor Metastasis and Augment Treatment Efficacy.

ABSTRACT

Cancer metastasis is the main cause of chemotherapeutic failure. Inhibiting the activity of matrix metalloproteinases (MMPs) is a common strategy for reducing metastasis. However, broad-spectrum MMP-inhibitors (MMPI) may cause undesired side effects. Here, we screened a selective MMP2 inhibitor (CCKIGLFRWR) and linked it with doxorubicin (DOX) to produce an amphiphilic peptide-drug conjugate (PDC). Then novel core-shell nanoparticles were self-assembled from PDC core and modified polylysine (MPL) shell. When the particles were passively targeted to the tumor site, the PDC core was exposed for charge switch of the MPL shell, aggregated for its transformation behavior, and specially adhered to the cell membrane. The disulfide bond between the MMPI peptide and DOX was broken via a low concentration of glutathione-mediated reduction in tumor microenvironment. DOX could effectively enter the tumor cells. Meanwhile, the MMPI peptide could selectively inhibit the activity of the MMP2 and effectively inhibit tumor metastasis.