Highly-Efficient Cellular Uptake and Membrane Permeability of Cell-Penetrating Peptides via Introduction of Homoarginine Residues.

The use of cell-penetrating peptides (CPPs) for the intracellular delivery of pharmaceuticals has progressed from basic research to global clinical studies. In this study, we investigated the effects of introducing l-homoarginine into the CPP oligoarginine on intracellular uptake and membrane permeability efficiency. We demonstrated that extending the arginine side chain by one methylene group (l-homoarginine) significantly increased the intracellular uptake of hexa-oligoarginine compared with extension of the main chain by one carbon atom (l-β-homoarginine). Incorporation of the l-homoarginine sequence improved the short-term stability of hexa-oligoarginine in fetal bovine serum. Furthermore, this strategy showed potential utility in boron neutron capture therapy; when used as an intracellular delivery vehicle, the l-homoarginine-containing peptide facilitated the intracellular delivery of therapeutic boron-containing agents and the effects of thermal neutron irradiation, resulting in increased cancer cell killing. These findings demonstrate that the introduction of l-homoarginine residues is an effective approach for improving the intracellular delivery efficiency and biological stability of CPPs.