Cell-Penetrating Peptide-Mediated Therapeutic Molecule Delivery into the Central Nervous System

Abstract

The blood-brain barrier (BBB), a dynamic and complex barrier formed by endothelial cells, can impede the entry of unwanted substances – pathogens and therapeutic molecules alike – into the central nervous system (CNS) from the blood circulation. Taking into account the fact that CNS-related diseases are the largest and fastest growing unmet medical concern, many potential protein- and nucleic acid-based medicines have been developed for therapeutic purposes. However, due to their poor ability to cross the BBB and the plasma membrane, the above-mentioned bio-macromolecules have limited use in treating neurological diseases. Finding effective, safe, and convenient ways to deliver therapeutic molecules into the CNS is thus urgently required. In recent decades, much effort has been expended in the development of drug delivery technologies, of which cell-penetrating peptides (CPPs) have the most promising potential. The present review covers the latest advances in CPP delivery technology, and provides an update on their use in CNS-targeted drug delivery.

Cell-penetrating peptides as a promising tool for delivery of various molecules into the cells

“…CPPs were recently used for the introduction of active agents across blood-brain barrier (BBB) [95], which is normally impermeable for most of the pharmaceutical substances at non-toxic concentrations [96]. For protein introduction, administration of Tat-JNKI1 fusion protein 3 hours after brain ischemia significantly reduced the infarct volume in mice [97].…”

“…SOCS3 protein introduced with FGF4-CPP protected mice from lethal effects of staphylococcal enterotoxin B and lipopolysaccharide by reducing production of inflammatory cytokines and hemorrhagic necrosis in brain [98]. In experiments with human patients with brain metastases, efficient introduction of anti-cancer drug, paclitaxel, was observed when conjugated to Angiopep-2 CPP [99]; significant uptake of doxorubicin was noted when the drug was conjugated either with Angiopep-5 [100] or SynB1/SynB5 CPPs [95,101].…”

A Simple Alternative to Stereotactic Injection for Brain Specific Knockdown of miRNA

“…The Rabies virus glycoprotein derived, RVG peptide is known to bind to the nicotinic acetylcholine receptor and has been used in combination with liposomes and nano-particles. The unique ability of this peptide to cross the blood brain barrier with minimal toxicity and carry siRNA, small molecules, anti-sense molecules or plasmid for delivery to the brain can be very useful in drug delivery to the CNS 8,15,16 . More specifically, a simple conjugate of the peptide with a modified anti-sense molecule, for CNS delivery of microRNA inhibitors by-passing the blood brain barrier can accelerate in vivo functional studies on neuronal miRNAs.…”

Therapeutic and diagnostic applications of extracellular vesicles

“…These authors showed that the VSV-G protein stimulated MHC I mediated antigen presentation and elicited an antigen-specific CD8 + T cell response [142]. The previously mentioned RVG targeting ligand [119,144,145] and iRGD [133,146] have also been reported to have membrane-destabilizing properties, possibly contributing to enhanced cytoplasmic delivery of the encapsulated cargo.…”