Cell-penetrating peptides as tools to enhance non-injectable delivery of biopharmaceuticals

Abstract

Non-injectable delivery of peptide and protein drugs is hampered by their labile nature, hydrophilicity, and large molecular size; thus limiting their permeation across mucosae, which represent major biochemical and physical barriers to drugs administered via e.g. the oral, nasal, and pulmonary routes. However, in recent years cell-penetrating peptides (CPP) have emerged as promising tools to enhance mucosal delivery of co-administered or conjugated peptide and protein cargo and more advanced CPP-cargo formulations are emerging. CPPs act as transepithelial delivery vectors, but the mechanism(s) by which CPPs mediate cargo translocation across an epithelium is so far poorly understood; both due to the fact that multiple factors influence the resulting uptake and trafficking mechanisms as well as to the complicated nature of sensitive studies of this. In addition to a proper mechanistic understanding, documentation of CPP-mediated delivery in higher animal species than rodent as well as extensive toxicological studies are necessary for CPP-containing non-injectable DDSs to reach the clinic.

Keywords: cell-penetrating peptides; delivery vectors; drug delivery; epithelium; mucosal barriers; non-injectable delivery; peptide and protein drugs.

Figure 1.

Simplified illustration representing suggested mechanisms for CPP-mediated delivery of peptide and protein cargos across epithelia. These include direct translocation, endocytosis followed by transcytosis, and paracellular translocation.