Ultrashort Cell-Penetrating Peptides for Enhanced Sonophoresis-Mediated Transdermal Transport

Lee Schnaider, Leah Shimonov, Topaz Kreiser, Dor Zaguri, Darya Bychenko, Itzchak Brickner, Sofiya Kolusheva, Alexandra Lichtenstein, Joseph Kost, Ehud Gazit*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


The skin is a key site for drug administration because of its large surface area and noninvasive accessibility. However, the dermal architecture serves as an excellent barrier, protecting from external mechanical, chemical, microbial, and physical perturbations. Most drugs display poor permeability through this barrier, thus making dermal and subdermal delivery challenging. Cell-penetrating peptides (CPPs), a diverse group of relatively short cationic and amphipathic membrane-interacting peptides, are fast becoming an important class of drug carriers and could potentially be developed for the dermal delivery of active molecules. However, the mechanism of CPP transdermal delivery is not fully understood, and there is a genuine need for a minimal model to understand this important phenomenon. Here, we demonstrate the potent membrane interactions of a minimal four-amino-acid-long CPP as well as the significance of guanidinium patterning and cationic nature of this palindromic peptide on its bioactivity. Furthermore, we demonstrate the biocompatibility of this peptide as well as its rapid cellular uptake and endosomal distribution. Finally, by utilizing a porcine full-thickness skin model, we demonstrate the substantial independent dermal and sonophoresis-based transdermal penetration of this minimal model. These results provide a minimal model for CPPs which can be easily manipulated for further biophysical and biochemical evaluations as well as a potent functional CPP with excellent skin permeability, which can be utilized for a wide variety of cosmetic and medical applications.

Original languageEnglish
Pages (from-to)8395-8401
Number of pages7
JournalACS Applied Bio Materials
Issue number12
StatePublished - 21 Dec 2020


FundersFunder number
Ministry of Science, Technology and Space


    • cell-penetrating peptides
    • diphenylalanine
    • membrane interactions
    • sonophoresis
    • transdermal delivery


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