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: 3.42). 12/2007; 24(11):1977-92. DOI: 10.1007/s11095-007-9303-7
Source: PubMed


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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    • "Since the first report in 19945, cell-penetrating peptides (CPPs) have been considered a promising delivery system, and there are currently several different methods of CPP intracellular delivery. The CPP also called protein transduction domains (PTDs) can deliver many types of cargo, such as oligonucleotides, small molecules, siRNA, nanoparticles, peptides and proteins, into cells678910. Generally, CPPs consist of short basic amino acid sequences with a net positive charge (usually lysine and arginine residues). "
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    ABSTRACT: Delivery of proteins has been regarded as the safest and most useful application in therapeutic application of stem cells, because proteins can regulate gene expression transiently without any genomic alteration. However, it is difficult to accurately measure efficiency or quantity of intracellular protein uptake. Here, we performed a comparison study of cell-penetrating peptide (CPP)-conjugated protein delivery system using seven arginine and Streptolysin O (SLO)-mediated system. To compare CPP- and SLO-mediated protein delivery systems, we used GFP and ESRRB protein, which is known to regulate pluripotency-related genes, for delivery into human bone marrow stromal cells (hBMSCs) and human testicular stromal cells (hTSCs). We found that CPP-conjugated protein delivery was more efficient, lower cytotoxicity, and higher biological activity than SLO-mediated protein delivery system. These results suggest that delivery of CPP-conjugated proteins is an efficient tool for introducing biologically active proteins into cells and may have important implications in clinical cell-based therapy.
    Scientific Reports 03/2014; 4:4378. DOI:10.1038/srep04378 · 5.58 Impact Factor
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    • "In the present study, we used a CPP protein delivery system known as protein transduction domains or membrane transduction peptides. They have been thought to be a useful tool due to their ability to translocate across cellular membranes [24]. They consist of short sequences of amino acids, such as arginine or lysine residues, which confer a positive charge to the CPPs [25]. "
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    ABSTRACT: Estrogen related receptor β (Esrrb) is a member of the orphan nuclear receptors and may regulate the expression of pluripotency-related genes, such as Oct4 and Nanog. Therefore, in the present study, we have developed a method for delivering exogenous ESRRB recombinant protein into embryos by using cell-penetrating peptide (CPP) conjugation and have analyzed their effect on embryonic development. Mouse oocytes and embryos were obtained from superovulated mice. The expression of Oct4 mRNA and the cell number of inner cell mass (ICM) in the in vitro-derived and in vivo-derived blastocysts were first analyzed by real time-reverse transcription-polymerase chain reaction and differential staining. Then 8-cell embryos were cultured in KSOM media with or without 2 µg/mL CPP-ESRRB protein for 24 to 48 hours, followed by checking their integration into embryos during in vitro culture by Western blot and immunocytochemistry. Expression of Oct4 and the cell number of ICM were lower in the in vitro-derived blastocysts than in the in vivo-derived ones (p<0.05). In the blastocysts derived from the CPP-ESRRB-treated group, expression of Oct4 was greater than in the non-treated groups (p<0.05). Although no difference in embryonic development was observed between the treated and non-treated groups, the cell number of ICM was greater in the CPP-ESRRB-treated group. Treatment of CPP-ESRRB during cultivation could increase embryos' expression of Oct4 and the formation rate of the ICM in the blastocyst. Additionally, an exogenous delivery system of CPP-conjugated protein would be a useful tool for improving embryo culture systems.
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