Publikationsdatenbank

Topical delivery of Tofacitinib in dermatology:
the promise of a novel therapeutic class using biodegradable dendritic polyglycerol sulfates (2024)

Art

Zeitschriftenartikel / wissenschaftlicher Beitrag

Autoren

Zabihi, Fatemeh

Cherri, Mariam

Guo, Xiao

Rancan, Fiorenza

Schumacher, Fabian

Mohammadifar, Ehsan

Kleuser, Burkhard

Bäumer, Wolfgang (WE 14)

Schirner, Michael

Vogt, Annika

Haag, Rainer

Quelle

Pharmaceuticals

Bandzählung: 17

Heftzählung: 1

Seiten: Artikelnummer: 77

ISSN: 1424-8247

Sprache

Englisch

Verweise

URL (Volltext): https://www.mdpi.com/1424-8247/17/1/77

DOI: 10.3390/ph17010077

Kontakt

Institut für Pharmakologie und Toxikologie

Koserstr. 20
14195 Berlin
+49 30 838 53221
pharmakologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

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