Lauroylated Histidine-Enriched S4-PV Peptide as an Efficient Gene Silencing Mediator in Cancer Cells

Purpose: This study aimed to endow the cell-penetrating peptide (CPP) S4-PV with adequate features towards a safe and effective application in cancer gene therapy. Methods: Peptide/siRNA complexes were prepared with two new derivatives of the CPP S4-PV, which combine a lauroyl group attached to the N- or C-terminus with a histidine-enrichment in the N-terminus of the S4-PV peptide, being named C12-H-S4-PV and H-S4-PV-C12, respectively. Physicochemical characterization of siRNA complexes was performed and their cytotoxicity and efficiency to mediate siRNA delivery and gene silencing in cancer cells were assessed in the absence and presence of serum. Results: Peptide/siRNA complexes prepared with the C12-H-S4-PV derivative showed a nanoscale (ca. 100 nm) particle size, as revealed by TEM, and efficiently mediated gene silencing (37%) in human U87 glioblastoma cells in the presence of 30% serum. In addition, the new C12-H-S4-PV-based siRNA delivery system efficiently downregulated stearoyl-CoA desaturase-1, a key-enzyme of lipid metabolism overexpressed in cancer, which resulted in a significant decrease in the viability of U87 cells. Importantly, these complexes were able to spare healthy human astrocytes. Conclusions: These encouraging results pave the way for a potential application of the C12-H-S4-PV peptide as a promising tool in cancer gene therapy.