Recombinant peptide constructs for targeted cell penetrating peptide-mediated delivery

Abstract

A recently designed nanoconstruct was engineered using recombinant technology to contain a cell-penetrating peptide (CPP), i.e. Model Amphipathic Peptide (MAP), attached to a pH-sensitive masking peptide sequence. CPPs such as MAP exhibit unique internalization properties which enable them to deliver attached bioactive molecules, including proteins and peptides, into the cytosolic or nuclear compartment of cells. However, their application in drug delivery is limited due to lack of specificity, as they are widely distributed in most tissues following in vivo administration. In order to overcome this hurdle, a highly pH-sensitive histidine-glutamic acid (HE) copolymer sequence was linked to MAP to prevent non-specific internalization of the construct in non-target cells. Our results show that this nanoconstruct is highly pH-sensitive in a mildly acidic pH, exhibiting high binding and internalization at pH 6.8 and below, but low binding and internalization at pH>7. This unique sensitivity in the mildly acidic pH range can be applied to targeting the activation of membrane permeable properties in mildly acidic pH environments, such as the surface of tumor cells or in the early endosomes of target cells. Therefore, the design could lead to a significant advancement in the application of CPPs and in the therapeutic potential of the biotechnology field.