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Delivery of Macromolecules Using Arginine-Rich Cell-Penetrating Peptides: Ways to Overcome Endosomal Entrapment

  • Emerging Drug Delivery Technologies
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Abstract

Arginine-rich cell-penetrating peptides (AR-CPPs) are very promising tools for the delivery of therapeutic macromolecules such as peptides, proteins, and nucleic acids. These peptides allow efficient internalization of the linked cargos intracellularly through the endocytic pathway. However, when linked to bulky cargos, entrapment in the endocytic vesicles is a major limitation to the application of these peptides in cytosolic delivery. Attachment of a compatible endosomal escape device is, therefore, necessary to allow cytosolic delivery of the peptide-attached cargo. This review presents different endosomal escape devices currently in application in combination with AR-CPPs. Applications of fusogenic lipids, membrane-disruptive peptides, membrane-disruptive polymers, lysosomotropic agents, and photochemical internalization to enhance the cytosolic delivery of AR-CPPs-attached cargos are presented. The properties of each system and its mechanism of action for the enhancement of endosomal escape are discussed, together with its applications for the delivery of different macromolecules in vitro and, if applicable, in vivo.

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Acknowledgements

The authors’ research was supported, in part, by Grants-in-Aid for Scientific Research (A) from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by Grants-in-Aid for Scientific Research on Priority Areas from the Japan Society for the Promotion of Science. The authors thank Dr. James L. McDonald for his helpful advice in writing the English manuscript.

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Authors and Affiliations

  1. Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-Ku, Sapporo, Hokkaido, 060-0812, Japan

    Ayman El-Sayed & Hideyoshi Harashima

  2. Institute for Chemical Research, Kyoto University, Uji, Kyoto, 611-0011, Japan

    Shiroh Futaki

  3. CREST, Japan Science and Technology Agency (JST), Kawaguchi, Saitama, 332-0012, Japan

    Ayman El-Sayed & Hideyoshi Harashima

Authors
  1. Ayman El-Sayed
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  2. Shiroh Futaki
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  3. Hideyoshi Harashima
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Correspondence to Hideyoshi Harashima.

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Guest Editor: Dexi Liu

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El-Sayed, A., Futaki, S. & Harashima, H. Delivery of Macromolecules Using Arginine-Rich Cell-Penetrating Peptides: Ways to Overcome Endosomal Entrapment. AAPS J 11, 13–22 (2009). https://doi.org/10.1208/s12248-008-9071-2

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  • DOI: https://doi.org/10.1208/s12248-008-9071-2

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