title: Skin Penetrating Peptide as a Tool to Enhance the Permeation of Heparin through Human Epidermis.
abstract: This study aimed to identify a new skin penetrating peptide (SPP) able to enhance unfractionated heparin (UFH) permeation through human epidermis by screening a phage display peptide library. The effects of the synthesized heptapeptide (DRTTLTN) on human stratum corneum organization were investigated by ATR-FTIR spectroscopy and molecular dynamics simulation. The DRTTLTN penetration within the human epidermis caused both a fluidization of the stratum corneum lipids and the extension of keratins due to the increase of the contribution of α-helices. The coadministration of DRTTLTN with UFH resulted ineffective in increasing skin penetration due to UFH affinity for keratins. The conjugation of DRTTLTN to UFH by N-(3-(dimethylamino)propyl)-N'-ethylcarbodiimide hydrochloride and sodium N-hydroxysulfosuccinimide led to an increase of the flux of 24-36-fold with respect to raw UFH, depending on the adopted synthetic procedure. The new compounds showed a decrease of the antifactor Xa activity of about 4-5 times. DRTTLTN also permitted to increase the fluxes of small model molecules. In conclusion, these data support the use of SPP to enhance the skin penetration of poorly absorbed compounds even in the case of macromolecules as polysaccharides.
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano , Via Giuseppe Colombo, 71-20133 Milan, Italy.
authors.forename: Chiara G M
authors.initials: CG
authors.lastname: Gennari
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano , Via Giuseppe Colombo, 71-20133 Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Franzè
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano , Via Giuseppe Colombo, 71-20133 Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Pellegrino
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano , Via Giuseppe Balzaretti, 9-20133 Milan, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Corsini
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano , Via Giuseppe Colombo, 71-20133 Milan, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Vistoli
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano , Via Giuseppe Colombo, 71-20133 Milan, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Montanari
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano , Via Giuseppe Colombo, 71-20133 Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Minghetti
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano , Via Giuseppe Colombo, 71-20133 Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cilurzo
mesh_terms: D000328:Adult; D004817:Epidermis / Q000378:metabolism*; D005260:Female; D006493:Heparin / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007633:Keratins / Q000378:metabolism; D008055:Lipids / Q000502:physiology; D008875:Middle Aged; D019151:Peptide Library; D010455:Peptides / Q000378:metabolism*; D010539:Permeability / Q000187:drug effects; D012867:Skin / Q000378:metabolism*; D012869:Skin Absorption / Q000187:drug effects; D017550:Spectroscopy, Fourier Transform Infrared / Q000379:methods
chemical_list: D008055:Lipids; D019151:Peptide Library; D010455:Peptides; D007633:Keratins; D006493:Heparin