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.

How Precise are Nanomedicines in Overcoming the Blood–Brain Barrier? A Comprehensive Review of the Literature

“… 137 Furthermore, intranasal administration has emerged as a widely utilized approach in pharmaceutical delivery owing to several benefits, including prompt absorption, rapid initiation of action, noninvasive nature, minimal tissue damage, and straightforward application. 138 This study revealed significant variations in the effectiveness of drug delivery among different intranasal delivery nanomaterials. These variations were mostly independent of the physicochemical features of the pharmaceuticals delivered.…”

“…With low cellular toxicity and high effectiveness, cell-penetrating peptide (CPP)-based delivery methods can successfully transport macromolecules across cellular membranes. 138 The BBB must be physically broken apart for the invasive mechanism to function, and nanomaterials must be transferred along paracellular channels to cross the BBB ( Figure 3 ). 153 The transient BBB disruption technique described above and local delivery strategy are part of the invasive mechanism, also known as the paracellular mechanism.…”

Intranasal Delivery of Anti-Apoptotic siRNA Complexed with Fas-Signaling Blocking Peptides Attenuates Cellular Apoptosis in Brain Ischemia

“…Rapid clearance by the mucociliary system can shorten the drug’s contact with the nasal mucosa, thereby reducing its absorption and bioavailability [ 64 ]. Some studies suggest that the nanocomplex may evade mucociliary clearance, potentially prolonging drug release [ 65 , 66 ]. This underscores the importance of better understanding mechanisms that can enhance nasal drug delivery efficacy.…”

Modeling brain pathology to study nose-to-brain drug delivery

“…As a result, the original pharmacological activity stays preserved. With the parenteral route of administration, the activity of the drug per se does not change, but its delivered volume passing through the blood-brain barrier becomes insufficient (7).…”