Article

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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    • "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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    • "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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