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.

Cyclic Dipeptide: A Privileged Molecular Scaffold to Derive Structural Diversity and Functional Utility

“…[95] Diclofenac is a non-steroidal anti-inflammatory drug (NSAID), which is administered (oral/intramuscular) as analgesic to reduce the pain in inflammatory conditions and dysmenorrhea. [95] The synthesis of cyclo(Phe-N-MeNal), cyclo (Phe-N-MeNal)-diclofenac (51) and TAT-diclofenac conjugates was achieved by following the routine solid phase synthesis protocols. [95] Cyclo (Phe-N-MeNal) was chosen to serve as a drug carrier vehicle into the skin as well as to enhance the permeability of diclofenac.…”

“…[95] The synthesis of cyclo(Phe-N-MeNal), cyclo (Phe-N-MeNal)-diclofenac (51) and TAT-diclofenac conjugates was achieved by following the routine solid phase synthesis protocols. [95] Cyclo (Phe-N-MeNal) was chosen to serve as a drug carrier vehicle into the skin as well as to enhance the permeability of diclofenac. This study signifies the broad utilities of CDP scaffolds as drug carrier vehicles.…”

“…In another report, delivery of CDP conjugated diclofenac (CDP‐diclofenac) into human epidermis is demonstrated [95] . Diclofenac is a non‐steroidal anti‐inflammatory drug (NSAID), which is administered (oral/intramuscular) as analgesic to reduce the pain in inflammatory conditions and dysmenorrhea [95] .…”

“…In another report, delivery of CDP conjugated diclofenac (CDP‐diclofenac) into human epidermis is demonstrated [95] . Diclofenac is a non‐steroidal anti‐inflammatory drug (NSAID), which is administered (oral/intramuscular) as analgesic to reduce the pain in inflammatory conditions and dysmenorrhea [95] . The synthesis of cyclo(Phe‐ N ‐MeNal), cyclo(Phe‐ N ‐MeNal)‐diclofenac ( 51 ) and TAT‐diclofenac conjugates was achieved by following the routine solid phase synthesis protocols [95] .…”

N‐methylation in amino acids and peptides: Scope and limitations

“…Taking advantage of the relative simplicity of Fukuyama's method, several research groups adapted this approach and used the solid support in the solid phase as temporary protection for the carboxyl group. Yang et al applied Fukuyama's strategy for the efficient preparation of NMAAs by using amino acids preloaded on 2‐Cl‐trityl (CTC) resin, which has been widely used for the synthesis of the fully protected peptide fragment (Scheme ) …”