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.
Highlights
Considerable research effort has been focused on the development of skin penetration enhancement approaches primarily directed at overcoming the stratum corneum barrier
We show that the novel peptide shuttle DKP increases permeation of diclofenac into and across human skin
We show that when conjugated to the DKP, diclofenac retains its COX-2 inhibition activity
Summary
Considerable research effort has been focused on the development of skin penetration enhancement approaches primarily directed at overcoming the stratum corneum barrier. These approaches focus on improving the physicochemical characteristics of the permeant within the skin, facilitating transport by improved solubility or disrupting the skin barrier [1]. Several carrier-mediated delivery systems have recently been developed including nanoparticles and flexible liposomes. There is considerable debate around the efficacy and/or mechanism of enhancement of these technologies with current evidence suggesting that nanoparticles are most useful for targeting skin appendages as they do not effectively permeate through intact skin [2]. Flexible liposomes enhance permeation primarily due to their lipid, surfactant and PLOS ONE | DOI:10.1371/journal.pone.0160973. Flexible liposomes enhance permeation primarily due to their lipid, surfactant and PLOS ONE | DOI:10.1371/journal.pone.0160973 August 22, 2016
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