Transdermal protein delivery by a coadministered peptide identified via phage display

Efficient transdermal drug delivery of large hydrophilic drugs is challenging. Here we report that the short synthetic peptide, ACSSSPSKHCG, identified by in vivo phage display, facilitated efficient transdermal protein drug delivery through intact skin. Coadministration of the peptide and insulin to the abdominal skin of diabetic rats resulted in elevated systemic levels of insulin and suppressed serum glucose levels for at least 11 h. Significant systemic bioavailability of human growth hormone was also achieved when topically coadministered with the peptide. The transdermal-enhancing activity of the peptide was sequence specific and dose dependent, did not involve direct interaction with insulin and enabled penetration of insulin into hair follicles beyond a depth of 600 μm. Time-lapse studies suggested that the peptide creates a transient opening in the skin barrier to enable macromolecular drugs to reach systemic circulation.

[1]  N. Weiner,et al.  Transfollicular Drug Delivery , 1995, Pharmaceutical Research.

[2]  R. Barrett,et al.  Peptides on phage: a vast library of peptides for identifying ligands. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[3]  O. Katare,et al.  The pilosebaceous unit: a pivotal route for topical drug delivery. , 2000, Methods and findings in experimental and clinical pharmacology.

[4]  J. Bos,et al.  The 500 Dalton rule for the skin penetration of chemical compounds and drugs , 2000, Experimental dermatology.

[5]  S. Kong,et al.  Antennapedia transduction sequence promotes anti tumour immunity to epicutaneously administered CTL epitopes. , 2004, Vaccine.

[6]  Samir Mitragotri,et al.  Discovery of transdermal penetration enhancers by high-throughput screening , 2004, Nature Biotechnology.

[7]  Adrian C. Williams,et al.  Penetration enhancers. , 2004, Advanced drug delivery reviews.

[8]  Erkki Ruoslahti,et al.  Organ targeting In vivo using phage display peptide libraries , 1996, Nature.

[9]  Aarti Naik,et al.  Iontophoretic drug delivery. , 2004, Advanced drug delivery reviews.

[10]  R. Hoffman,et al.  The feasibility of targeted selective gene therapy of the hair follicle , 1995, Nature Medicine.

[11]  E. Ruoslahti,et al.  Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. , 1998, Science.

[12]  Lokesh Joshi,et al.  Comparative Study of the Skin Penetration of Protein Transduction Domains and a Conjugated Peptide , 2005, Pharmaceutical Research.

[13]  S. Mitragotri,et al.  Current status and future potential of transdermal drug delivery , 2004, Nature Reviews Drug Discovery.

[14]  B. Shroot,et al.  Site-Specific Drug Delivery to Pilosebaceous Structures Using Polymeric Microspheres , 1993, Pharmaceutical Research.

[15]  V. Uversky,et al.  Prediction of the association state of insulin using spectral parameters. , 2003, Journal of pharmaceutical sciences.

[16]  Joseph Kost,et al.  Ultrasound and transdermal drug delivery. , 2004, Drug discovery today.

[17]  S. Rafii,et al.  Tumor vasculature address book: identification of stage-specific tumor vessel zip codes by phage display. , 2003, Cancer cell.

[18]  Eric W. Smith,et al.  Penetration enhancement of transdermal delivery--current permutations and limitations. , 2004, Critical reviews in therapeutic drug carrier systems.

[19]  B. Solomon,et al.  Filamentous phage as vector-mediated antibody delivery to the brain , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[20]  J. Rothbard,et al.  Conjugation of arginine oligomers to cyclosporin A facilitates topical delivery and inhibition of inflammation , 2000, Nature Medicine.

[21]  Mark R Prausnitz,et al.  Microneedles for transdermal drug delivery. , 2004, Advanced drug delivery reviews.

[22]  R. Scheuplein,et al.  Permeability of the skin. , 1971, Physiological reviews.

[23]  W. J. Irwin,et al.  Low Intensity Ultrasound as a Probe to Elucidate the Relative Follicular Contribution to Total Transdermal Absorption , 2004, Pharmaceutical Research.

[24]  Samir Mitragotri,et al.  Design principles of chemical penetration enhancers for transdermal drug delivery. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[25]  J. Bouwstra,et al.  Penetration and distribution of three lipophilic probes in vitro in human skin focusing on the hair follicle. , 2002, Journal of controlled release : official journal of the Controlled Release Society.

[26]  A. Prochiantz,et al.  Transduction peptides: from technology to physiology , 2004, Nature Cell Biology.

[27]  S. J. White,et al.  Identification of peptide sequences that induce the transport of phage across the gastrointestinal mucosal barrier. , 2004, Journal of virological methods.

[28]  B. Finnin,et al.  The transdermal revolution. , 2004, Drug discovery today.

[29]  William Montagna,et al.  The Structure and Function of Skin , 1956, The Yale Journal of Biology and Medicine.