title: Rational design of CPP-based drug delivery systems: considerations from pharmacokinetics.
abstract: Therapeutics are restricted from cellular internalization due to the biological barrier formed by the cell membrane. Especially for therapeutics with high molecular weight, strategies are required to enable delivery to intracellular targets. Cell-penetrating peptides (CPPs) represent a powerful tool to mediate the entry of large cargos such as proteins, siRNA and nanoparticles. The high diversity of CPPs is the prerequisite to use this class of carriers for various applications. However, therapies based on CPPs are hampered by their unfavorable pharmacokinetics, mainly dominated by their rapid renal clearance and their lack of specificity. Rational design is required to overcome these disadvantages and thereby exploits the actual potential of CPPs. We summarize and highlight the current state of knowledge with special emphasis on pharmacokinetics. The unclear internalization pathways of CPPs remain one of the main obstacles and therefore have been in the focus of research. In this review, several promising strategies such as the combination with targeting sequences, activatable CPPs and adjustment of the molecular weight are described. In addition, new absorption pathways such as nasal, pulmonary or transdermal uptake expand the applicability of CPPs and may be a promising prospect for clinical application.
authors.forename: Arite
authors.initials: A
authors.lastname: Mickan
authors.forename: Dikran
authors.initials: D
authors.lastname: Sarko
authors.forename: Uwe
authors.initials: U
authors.lastname: Haberkorn
authors.affiliation: Department of Nuclear Medicine, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany. walter.mier@med.uni-heidelberg.de.
authors.forename: Walter
authors.initials: W
authors.lastname: Mier
mesh_terms: D000818:Animals; D057846:Cell-Penetrating Peptides / Q000097:blood / Q000737:chemistry / Q000145:classification / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D014018:Tissue Distribution
chemical_list: D057846:Cell-Penetrating Peptides