title: Cyclic Dipeptide Shuttles as a Novel Skin Penetration Enhancement Approach: Preliminary Evaluation with Diclofenac.
abstract: This study demonstrates the effectiveness of a peptide shuttle in delivering diclofenac into and through human epidermis. Diclofenac was conjugated to a novel phenylalanyl-N-methyl-naphthalenylalanine-derived diketopiperazine (DKP) shuttle and to TAT (a classical cell penetrating peptide), and topically applied to human epidermis in vitro. DKP and TAT effectively permeated into and through human epidermis. When conjugated to diclofenac, both DKP and TAT enhanced delivery into and through human epidermis, though DKP was significantly more effective. Penetration of diclofenac through human epidermis (to receptor) was increased by conjugation to the peptide shuttle and cell penetrating peptide with enhancement of 6x by DKP-diclofenac and 3x by TAT-diclofenac. In addition, the amount of diclofenac retained within the epidermis was significantly increased by peptide conjugation. COX-2 inhibition activity of diclofenac was retained when conjugated to DKP. Our study suggests that the peptide shuttle approach may offer a new strategy for targeted delivery of small therapeutic and diagnostic molecules to the skin.
authors.affiliation: School of Pharmacy, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia.|Therapeutics Research Centre, The University of Queensland, School of Medicine, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Yousuf
authors.initials: Y
authors.lastname: Mohammed
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona Science and Technology Institute (BIST), Barcelona, Spain.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Teixidó
authors.affiliation: Therapeutics Research Centre, The University of Queensland, School of Medicine, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Sarika
authors.initials: S
authors.lastname: Namjoshi
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona Science and Technology Institute (BIST), Barcelona, Spain.
authors.forename: Ernest
authors.initials: E
authors.lastname: Giralt
authors.affiliation: School of Pharmacy, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia.
authors.forename: Heather
authors.initials: H
authors.lastname: Benson
mesh_terms: D061645:Abdominoplasty; D000328:Adult; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D004008:Diclofenac / Q000378:metabolism / Q000494:pharmacology; D015194:Diffusion Chambers, Culture; D004151:Dipeptides / Q000737:chemistry / Q000378:metabolism*; D004337:Drug Carriers; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D015696:Gene Products, tat / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism*; D010539:Permeability; D010879:Piperazines / Q000737:chemistry*; D060327:Solid-Phase Synthesis Techniques; D046509:Tissue Culture Techniques
chemical_list: D016861:Cyclooxygenase Inhibitors; D004151:Dipeptides; D004337:Drug Carriers; D015696:Gene Products, tat; D010456:Peptides, Cyclic; D010879:Piperazines; D004008:Diclofenac; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human