Topical Delivery of Tofacitinib in Dermatology: The Promise of a Novel Therapeutic Class Using Biodegradable Dendritic Polyglycerol Sulfates.
Fatemeh ZabihiMariam CherriXiao GuoFiorenza RancanFabian SchumacherEhsan MohammadifarBurkhard KleuserWolfgang BäumerMichael SchirnerAnnika VogtRainer HaagPublished in: Pharmaceuticals (Basel, Switzerland) (2024)
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.
Keyphrases
- rheumatoid arthritis
- wound healing
- cell proliferation
- aqueous solution
- signaling pathway
- atopic dermatitis
- drug delivery
- transcription factor
- ulcerative colitis
- immune response
- anti inflammatory
- soft tissue
- epithelial mesenchymal transition
- cell therapy
- single cell
- stem cells
- genome wide
- pseudomonas aeruginosa
- toll like receptor
- gene expression
- staphylococcus aureus
- cystic fibrosis
- dna methylation
- mass spectrometry
- high resolution
- bone marrow
- nuclear factor
- tyrosine kinase
- big data
- inflammatory response
- functional connectivity
- candida albicans
- resting state