Rationally designed cationic amphiphilic peptides for selective gene delivery to cancer cells.

Gene therapy has gained increasing attention as an alternative to pharmacotherapy for treatment of various diseases. The extracellular and intracellular barriers to gene delivery necessitate the use of gene vectors which has led to the development of myriads of gene delivery systems. However, many of these gene delivery systems have pitfalls such as low biocompatibility, low loading efficiency, low transfection efficiency, lack of tissue selectivity and high production costs. Herein, we report the development of a new series of short cationic amphiphilic peptides with anticancer activity for selective delivery of small interfering RNA (siRNA) and antisense oligodeoxynucleotides (ODNs) to cancer cells. The peptides consist of alternating dyads of hydrophobic (isoleucine (I) or leucine (L)) and hydrophilic (arginine (R) or lysine (L)) amino acids. The peptides exhibited higher preference for transfection of HCT 116 colorectal cancer cells compared to human dermal fibroblasts (HDFs) and induced higher level of gene silencing in the cancer cells. The nucleic acid complexation and transfection efficiency of the peptides was a function of their secondary structure, their hydrophobicity and their C-terminal amino acid. The peptides containing L in their hydrophobic domain formed stronger complexes with siRNA and successfully delivered it to the cancer cells but were unable to release their cargo inside the cells and therefore could not induce any gene silencing. On the contrary, the peptides containing I in their hydrophobic domain were able to release their associated siRNA and induce considerable gene silencing in cancer cells. The peptides exhibited higher selectivity for colorectal cancer cells and induced less gene silencing in fibroblasts compared to the lipid-based commercial transfection reagent DharmaFECT™ 1. The results from this study can serve as a tool for rational design of new peptide-based gene vectors for high selective gene delivery to cancer cells.