Cell Penetrating Peptides: Intracellular Pathways and Pharmaceutical Perspectives

Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California 90089, USA.
Pharmaceutical Research (Impact Factor: 3.95). 12/2007; 24(11):1977-92. DOI: 10.1007/s11095-007-9303-7
Source: PubMed

ABSTRACT Cell penetrating peptides, generally categorized as amphipathic or cationic depending on their sequence, are increasingly drawing attention as a non-invasive delivery technology for macromolecules. Delivery of a diverse set of cargo in terms of size and nature ranging from small molecules to particulate cargo has been attempted using different types of cell penetrating peptides (CPPs) in vitro and in vivo. However, the internalization mechanism of CPPs is an unresolved issue to date, with dramatic changes in view regarding the involvement of endocytosis as a pathway of internalization. A key reason for the lack of consensus on the mechanism can be attributed to the methodology in deciphering the internalization mechanism. In this review, we highlight some of the methodology concerns, focus more on the internalization pathway and also provide a novel perspective about the intracellular processing of CPPs, which is a crucial aspect to consider when selecting a cell penetrating peptide as a drug delivery system. In addition, recent applications of cell penetrating peptides for the delivery of small molecules, peptides, proteins, oligonucleotides, nanoparticles and liposomes have been reviewed.

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    • "[45] Some of the internalization mechanisms proposed for the cellular uptake of CPPs include endocytosis and direct translocation or cell penetration. [46] CPP-based systems appear to be very versatile and efficient. "
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    ABSTRACT: Antisense oligonucleotides are synthetic genetic materials that interact with natural genetic material and modulate them in a systematic way. Antisense oligonucleotides as a form of molecular medicine to modulate gene function was first acknowledged in the late 1970s. This therapy involves blocking translation, thereby inhibiting protein formation. Recently, antisense technology has been resurrected and has generated considerable enthusiasm in the research. Antisense oligonucleotides have proven to be valuable in gene functionalization and target validation and also represent a novel therapeutic strategy for wide range of diseases such as genetic disorders, cancers, and infectious diseases. Thus, in the present review an attempt is made to help the apprentice understand the basic concept of the antisense technology and its therapeutic applications.
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    • "Currently, many naturederived , synthetic, and chimeric peptides have been identified for their cell penetrating ability [4] [5], either alone or conjugated with other cargo molecules [6e10]. Although the internalization mechanism for CPPs is sequence and cargo dependent [11] [12], the ubiquitous uptake of CPPs by all kinds of cells has been found in vitro and in vivo [13]. However, the universal effectiveness of CPPs regardless of cell type also reflects their lack of specificity e a major hurdle for application in vivo. "
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    ABSTRACT: Cell penetrating peptides (CPPs) have been well established as potential carriers for intracellular delivery of protein/peptide therapeutics. However, their lack of selectivity impedes their application in vivo. In order to increase their specificity, a highly pH-sensitive histidine-glutamate (HE) co-oligopeptide was fused with a CPP, i.e. model amphipathic peptide (MAP), and was expressed as a fusion protein with glutathione S-transferase (GST) acting as a cargo protein. Compared with two other fusion proteins containing either HE or MAP, only the fused peptide (HE-MAP) could effectively deliver the cargo GST protein to cells at pH 6.5 or below, while maintaining low delivery to cells at pH 7.0 and above. Using a xenograft mouse model of human breast cancer, fluorescent imaging showed that only HE-MAP could effectively target GST to the tumor site, while reducing non-specific association of MAP in other organs. The data presented in this report demonstrate the diagnostic and/or therapeutic potential of the fused peptide, HE-MAP, for targeting the acidic tumor microenvironment. The concise design for this pH-sensitive peptide offers a simple way to overcome CPP's lack of selectivity, which could lead to increased application of CPPs and macromolecular therapeutics.
    Biomaterials 02/2014; 35(13). DOI:10.1016/j.biomaterials.2014.01.047 · 8.31 Impact Factor
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    • "Therefore these molecules present a great potential in therapeutics and diagnosis. Indeed, the number of applications using CPPs is quickly increasing, with so far more than 300 studies from in vitro to in vivo using CPP-based strategies [2] [3] [4] [5] [6]. Since their discovery in the 1990s an important number of research groups have focused in the understanding of their mode of action with the final attempt of improving their internalization and specificity. "
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    ABSTRACT: Cell penetrating peptides (CPPs) are usually short, highly cationic peptides that are capable of crossing the cell membrane and transport cargos of varied size and nature in cells by energy- and receptor-independent mechanisms. An additional potential is the newly discovered anti-tumor activity of certain CPPs, including RW16 (RRWRRWWRRWWRRWRR) which is derived from penetratin and is investigated here. The use of CPPs in therapeutics, diagnosis and potential application as anti-tumor agents increases the necessity of understanding their mode of action, a subject yet not totally understood. With this in mind, the membrane interaction and perturbation mechanisms of RW16 with both zwitterionic and anionic lipid model systems (used as representative models of healthy vs tumor cells) was investigated using a large panoply of biophysical techniques. It was shown that RW16 autoassociates and that its oligomerization state highly influences its membrane interaction. Overall a stronger association and perturbation of anionic membranes was observed, especially in presence of oligomeric peptide, when compared to zwitterionic ones. This might explain, at least in part, the anti-tumor activity and so the selective interaction with cancer cells whose membranes have been shown to be especially anionic. Hydrophobic contacts between the peptide and lipids were also shown to play an important role in the interaction. That probably results from the tryptophan insertion into the fatty acid lipid area following a peptide flip after the first electrostatic recognition. A model is presented that reflects the ensemble of results.
    Biochimica et Biophysica Acta 02/2013; 1828(6). DOI:10.1016/j.bbamem.2013.02.008 · 4.66 Impact Factor
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