Cell-Penetrating Peptides as Valuable Tools for Nose-to-Brain Delivery of Biological Drugs

Abstract

Due to their high specificity toward the target and their low toxicity, biological drugs have been successfully employed in a wide range of therapeutic areas. It is yet to be mentioned that biologics exhibit unfavorable pharmacokinetic properties, are susceptible to degradation by endogenous enzymes, and cannot penetrate biological barriers such as the blood-brain barrier (i.e., the major impediment to reaching the central nervous system (CNS)). Attempts to overcome these issues have been made by exploiting the intracerebroventricular and intrathecal routes of administration. The invasiveness and impracticality of these procedures has, however, prompted the development of novel drug delivery strategies including the intranasal route of administration. This represents a non-invasive way to achieve the CNS, reducing systemic exposure. Nonetheless, biotherapeutics strive to penetrate the nasal epithelium, raising the possibility that direct delivery to the nervous system may not be straightforward. To maximize the advantages of the intranasal route, new approaches have been proposed including the use of cell-penetrating peptides (CPPs) and CPP-functionalized nanosystems. This review aims at describing the most impactful attempts in using CPPs as carriers for the nose-to-brain delivery of biologics by analyzing their positive and negative aspects.

Keywords: cell-penetrating peptides; nose-to-brain administration; rehabilitation; therapy.

Figure 1

Schematic drawings representing the cell-penetrating peptide (CPP)-based technologies. The hydrophilic nature of effectors/cargoes (blue) such as peptides, proteins, nucleic acids, or small drugs can prevent their cellular uptake and hamper their access to intracellular targets. Conjugating the effector (cargo) to a CPP (orange) by covalent bonds or noncovalent complex formation enables the CPP–effector conjugate (CPP-conjugated therapeutic) to cross the cell membrane and reach intracellular areas that are difficult to access, thereby enhancing the therapeutic effectiveness. Reprinted from Ref. [4]. Copyright 2017, with permission from Elsevier.

Figure 2

Schematic representation of the proposed mechanisms for CPP internalization. Energy-independent pathways involving the membrane insertion of CPPs through pore formation and membrane destabilization are outlined in green. Energy-dependent models, or endocytic pathways such as macropinocytosis, clathrin-mediated endocytosis, caveolae-mediated endocytosis, and caveolae/clathrin-independent endocytosis are outlined in blue.

Figure 3

Schematic representation of the different routes described for N2B delivery. Upon administration in the nasal cavity, a drug (black dots) can reach the CNS via (i) an intracellular pathway, being endocytosed by either a neuron or a supporting cell and then shuttled to the CNS, or (ii) an extracellular pathway, travelling through the space between the olfactory neuron axons and the supporting cells or between two supporting cells. Once the nasal epithelium is crossed and the lamina propria is reached, drugs can also enter the blood or lymphatic vessels and join the systemic circulation, reaching peripheral organs.