Redox-Responsive Multifunctional Polypeptides Conjugated with Au Nanoparticles for Tumor-Targeting Gene Therapy and Their 1 + 1 > 2 Synergistic Effects.

Gene therapy is regarded as one of the most potential technologies for tumor therapy. Gene delivery systems with high specificity and good biocompatibility are urgently demanded. Hence, in this research, we designed and synthesized a series of tumor targeting and redox-responsive gold nanoparticles conjugated with three kinds of functional polypeptides (AuNPPs) that consisted of targeting peptide GE11, cell-penetrating peptide octaarginine (R8), and polyhistidine. All the AuNPPs exhibited superior cancer cellular internalization ability and targeting gene transfection efficiency compared with commercial agent BPEI 25K. It is interesting to find that different relative positions of GE11 and R8 can cause the change of target ability and gene transfection efficiency, and the suitable relative position of R8 and GE11 can not only endow the gene vector with functions that peptides previously own but also bring the synergistic effects. The best-performed AuNPP6-1 was chosen to transport the epidermal growth factor receptor (EGFR)-shRNA into A549 tumor-bearing BALB/c nude mice, and in vivo fluorescence imaging showed AuNPP6-1 mainly accumulated in tumor sites and achieved a great targeting therapy effect. These results provide significantly important information on understanding and constructing the tumor-targeting gene vector.