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Skin provides an easily accessible route for drug delivery without first-pass metabolism. To achieve transcutaneous drug delivery, it is often required to overcome the low permeability of the SC. One common strategy is to employ penetration enhancers which act to increase drug passage across the SC and to decrease the barrier resistance.

CPEs act by multiple postulated mechanisms; solubilizing the intercellular lipid matrix, disrupting the protein component of the intracellular keratin domains, and increasing drug partitioning into the tissue by acting as a solvent for the permeant within the membrane [12]. As a result, CPEs can cause skin irritation and safety concerns related to the health of the skin barrier. Many different classes of compounds have been proposed as CPE, including fatty acids (e.g., dodecanoic acid, stearic acid, oleic acid), surfactants (e.g., sodium dodecyl sulfate), azone (e.g., laurocapram), osmolytes (e.g., urea and glycols, including propylene glycol), and monoterpenes (e.g., thymol, carvacrol, and geraniol) [13, 14]. These compound classes are different with respect to their chemical and physical properties, and therefore expected to influence the SC molecular properties in different ways. Fatty acids, surfactant, and monoterpenes mainly affect SC lipids while osmolytes affect both SC lipid and protein components [15]. The irritation response of CPEs correlates with their ability to denaturize SC proteins [15]. Furthermore, molecular effects of added compounds on SC depend on SC hydration. The addition of water leads to increased molecular mobility of both protein and lipid components of the SC. Increasing fluidity is expected to lead to higher permeability for both polar and nonpolar compounds [16]. The main part of both the lipid and the keratin components are solid. In hydrated conditions, minor fractions of the SC lipid and protein components become fluid. Furthermore, the fluidity in these components can also be altered by the addition of compounds like urea or glycerol which are constituents of the natural moisturizing factor.

Cell-penetrating peptides (CPPs), also known as protein transduction domains, have garnered wide attention in recent years and emerged as a simple and effective noninvasive strategy for macro-molecule delivery into the skin [17]. Although CPPs have demonstrated their potential in enhancing skin delivery, they are still evolving as a new class of skin penetration enhancers. CPPs are relatively short (up to 30 amino acids in length), water soluble, cationic, and/or amphipathic peptides that are capable of carrying large macromolecules across cellular membranes [17]. CPPs have been increasingly used to mediate the delivery of molecular cargoes such as small molecules, small interfering RNA nucleotides, drug-loaded nanoparticles, proteins, and peptides without using any receptors and without causing any significant membrane damage [18]. These peptides are capable of internalizing electrostatically or covalently bound biologically active cargoes with high efficiency and minimal toxicity [19].