During the last decade, Cell-Penetrating Peptides (CPPs) have been investigated for their ability to overcome the cell membrane barrier for the intracellular or transcellular delivery of cargoes, such as many low molecular weight drugs, imaging agents, peptides, oligonucleotides, proteins and colloidal carriers such as liposomes and polymeric nanoparticles. Their ability to cross biological plasma membranes, especially in a non-disruptive way without apparent toxicity is highly desired for increasing drug bioavailability. Attempts have been made to extract related structural information that would predict mechanism of the uptake process of the transport peptides. For example, positive charges in side chains of Arg/Lys, presence of Trp or Phe residues in certain positions, amphiphilicity of the peptide, and length of the polypeptide chain have been proposed as important factors determining cellular uptake. However, despite numerous studies carried out in the field, the mechanism of uptake of CPPs is still not clarified. Therefore, rational design of novel transport peptides, such as comparison of positive-charges-containing CPPs and neutralized form CPPs, sequence of cationic amino acid residues and the role of clustering of net positive charges will be necessary for successful application of CPPs in research and therapy.

Application of CPPs.
A major obstacle in the development of new therapeutic agents is the low bioavailability of hydrophilic substances. It is well known that, drugs that bind to intracellular targets must penetrate the lipid bilayer membrane surrounding the cell in order to exert their effect. Fortunately, a relatively new research area that addresses this problem by introducing novel transport peptides, which attract many researchers in this field, has emerged. Most researchers look at the delivery of many therapeutic molecules by various CPPs, and their potential therapeutic application in a wide range of areas. These peptides predominantly have a positive net charge and/or an amphipathic nature, but can otherwise have very different characteristics and with the ability to cross the plasma membranes of mammalian cells in an apparently energy- and receptor-independent fashion compared to receptor-mediated carriers. This group of peptides, also sometimes called protein transduction domains (PTDs), is here referred to as cell-penetrating peptides (CPPs). As mentioned previously, the limited therapeutic value of polypeptides and oligonucleotides in biomedical research and as pharmaceutical substances is due to their low biomembrane permeability and their relatively rapid degradation. So people expect that the possibility to manipulate intracellular biological targets would increase if large-sized hydrophobic molecules could be addressed intracellularly, without severe limitation on amounts inherent to the necessity to cross membrane lipid bilayers. Thus, the discovery that CPPs translocate across the plasma membrane of live cells and permit intracellular transport of cargoes, such as conjugated peptides, proteins, oligonucleotides and nanoparticles, although in a still not clarified way, has opened new possibilities and proposed new hopes in biomedical research and therapy.

Although there is much debate over the mechanism by which this “protein transduction” occurs, the ability of CPPs to translocate rapidly into cells is being exploited to deliver a broad range of therapeutics in a variety of situations and biological systems. The ability CPPs to deliver different cargoes in a relatively efficient and non-invasive manner has implications as far reaching as drug delivery, gene transfer, DNA vaccination and beyond. Although many questions remain to be answered and limitations on the use of CPPs exist, it is clear that this emerging technology has much to offer in a clinical setting.

 

Reference:

Ling Ren. COMPARISON OF CELLULAR UPTAKE OF ARGININE-RICH CELL-PENETRATING PEPTIDES