Smart and selective cancer-killing peptides with cell penetrating sequence and dual-targeting mechanism

[Display omitted] A series of amphiphilic peptides with sequence of Ac-RGDGPLGLAGI3GRn-NH2 (n = 4, 6, 8) have been designed for the aim of selective cancer-killing. These molecules have four functional segments, the integrin-binding segment of RGD, the enzyme-cleavable segment of PLGLA, the hydrophobic segment of I3, and the cell membrane-penetrating segment of octa-arginine. Among them, the peptide with n = 8 (RR-22) turns out to be a ‘smart’ molecule with high efficiency in killing cancer cells and negligible cytotoxicity to normal cells. The concentration causing 50% cancer cell growth inhibition (IC50) is 50 μM for HeLa, 41 μM for Hpeg2, and 44 μM for A549, respectively. The high cancer-killing selectivity is ascribed to the dual cancer-targeting function, that is, the specific recognition and binding of RGD segment to cancer membranes and the cleavage of PLGLA segment by the cancer-overexpressed matrix metalloproteinase-7 (MMP7). This study illustrates an effective strategy for designing smart therapeutic molecules with both selectivity and targeting ability.