Improvement of Cell Penetrating Peptide for Efficient siRNA Targeting of Tumor Xenografts in Zebrafish Embryos

Abstract

Cell-penetrating peptides (CPPs) are one of the most efficient vectors for achieving cellular uptake of different cargos. However, their application in cancer therapy is greatly limited due to the lack of tissue selectivity, as they are widely distributed in most tissues following in vivo administration. To introduce specificity and improve tumor targeting, a combination of a cell-penetrating peptide (CADY) and a targeting ligand, the laminin receptor binding peptide (YIGSR) to target the 37/67 kDa laminin receptor, known to be upregulated in most cancer cells and to be correlated with the invasiveness and metastatic potential, is formulated. The targeting CPP named “Y-CADY” does not induce any change in the physico-chemical properties (secondary structure, small interference RNA (siRNA) complexation, size, and charge) of CADY. Interestingly, Y-CADY is more efficient than CADY for gene silencing in cell lines, and more potent for targeting and for inducing apoptosis of tumor xenografts in zebrafish embryos. The present study demonstrates that the novel targeting CPP “Y-CADY” is efficient for gene silencing and can serve as a vector to target cancer cells in vivo.