Modulating Protein-Protein Interactions In Vivo via Peptide-Lanthanide-Derived Nanoparticles for Hazard-Free Cancer Therapy.

ABSTRACT

Protein-protein interactions (PPIs) play an important role in almost all vital processes involved in many diseases, especially cancer. Peptides are perfect candidates that modulate PPIs as they can closely mimic principle features of protein. However, the intrinsic drawbacks of peptides, including poor stability and member impenetrability, severely limit the development of peptide-derived therapeutics. Nanotechnology offers a feasible route for anti-cancer peptide delivery, but much remains to be done, especially with respect to the pressing need for a simple method for efficient delivery of peptides into sites of interest towards potent and safe therapy. Herein, we report a one-step method to conjugate lanthanide-doped nanoparticles with p53-activating peptide (PMI TSFAEYWALLSP), Bcl2-blocking peptide (BIM IWIAQELRRIGDEFNAYYARR) and CD13-binding peptide (iNGR CRNGRGPDC) by mercaptogenic self-assembly. The resultant LDN-iNGRPMI-BIM nanoparticles can tumor-specifically accumulate at interest sites, and potently induce apoptosis of cancer cells in vitro and in vivo, while keeping a favorable biosafety profile. Taken together, the general therapeutically viable method reported here will enable us to develop a novel class of peptide-based nanomedicines, and likely reinvigorate peptide drug discovery efforts in general, which will target intracellular protein-protein interactions responsible for initiation and progression of a great variety of human diseases.