Inflammatory
skin diseases, such as
psoriasis,
atopic dermatitis, and
alopecia areata, occur when the regulatory tolerance of the innate immune system is disrupted, resulting in the activation of the
Janus kinase-signal transducer and activator of transcription (JAK-STAT) inflammatory signaling pathway by
interleukin 6 (IL-6) and other key inflammatory
cytokines.
JAK inhibitors, such as
tofacitinib, bind to these
enzymes which are coupled to receptors on cell surfaces and block the transcription of inflammatory
cytokine-induced genes. The first topical applications are being marketed, yet insufficient effects regarding indications, such as
alopecia areata, suggest that improved delivery technologies could help increase the efficacy. In this study, we used sulfated dendritic
polyglycerol with
caprolactone segments integrated in its backbone (dPGS-PCL), with a molecular weight of 54 kDa, as a degradable carrier to load and solubilize the hydrophobic drug
tofacitinib (TFB). TFB loaded in dPGS-PCL (dPGS-PCL@TFB), at a 11 w/w% loading capacity in aqueous
solution, showed in an ex-vivo human skin model better penetration than free TFB in a 30:70 (v/v)
ethanol/water mixture. We also investigated the anti-inflammatory efficacy of dPGS-PCL@TFB (0.5 w/w%), dPGS-PCL, and free TFB in the water/
ethanol mixture by measuring their effects on
IL-6 and
IL-8 release, and STAT3 and STAT5 activation in ex vivo skin models of simulated inflamed human skin. Our results suggest that dPGS-PCL@TFB reduces the activation of STAT3 and STAT5 by increasing the penetration of the
tofacitinib. However, no statistically significant differences with respect to the inhibition of
IL-6 and
IL-8 were observed in this short incubation time.