title: Cationic PTD/CPP-mediated macromolecular delivery: charging into the cell.
abstract: BACKGROUND
  Macromolecular therapeutics, including enzymes, transcription factors, siRNAs, peptides and large synthetic molecules, can potentially be used to treat human diseases by targeting intracellular molecular pathways and modulating biological responses. However, large macromolecules have no ability to enter cells and require delivery vehicles. Protein transduction domains (PTDs), also known as cell-penetrating peptides (CPPs), are a diverse class of peptides that can deliver macromolecules into cells.
  
  
  METHODS
  In this review, we cover the uptake and usage of arginine-rich PTDs/CPPs (TAT-PTD, Penetratin/Antp and 8R). We review the endocytosis-mediated uptake of these peptides and highlight three important steps: i) cell association; ii) internalization and iii) endosomal escape. We also discuss the array of different cargos that have been delivered by cationic PTDs/CPPs as well as cellular processes and biological responses that have been modulated.
  
  
  CONCLUSIONS
  PTDs/CPPs have shown great potential to deliver otherwise undeliverable macromolecular therapeutics into cells for experimentation in cell culture and in animal disease models in vivo. Moreover, over 25 clinical trials have been performed predominantly using the TAT-PTD. However, more work is still needed. Endosomal escape and target-cell specificity remain two of the major future challenges.
authors.affiliation: a 1 UCSD School of Medicine, Department of Cellular and Molecular Medicine , 9500 Gilman Dr., La Jolla, CA 92093-0686, USA sdowdy@ucsd.edu.|b 2 Uppsala University, Science for Life Laboratory, Department of Immunology, Genetics and Pathology , SE-751 08 Uppsala, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Lönn
authors.affiliation: a 1 UCSD School of Medicine, Department of Cellular and Molecular Medicine , 9500 Gilman Dr., La Jolla, CA 92093-0686, USA sdowdy@ucsd.edu.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Dowdy
mesh_terms: D000818:Animals; D002352:Carrier Proteins; D002412:Cations; D057846:Cell-Penetrating Peptides / Q000737:chemistry*; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000502:physiology; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D046911:Macromolecular Substances / Q000008:administration & dosage*; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D002412:Cations; D057846:Cell-Penetrating Peptides; D046911:Macromolecular Substances; D034741:RNA, Small Interfering; C414409:penetratin
keywords: CPP; PTD; delivery; macromolecular therapeutics