Toxicity of topically applied drugs beyond skin irritation: Static skin model vs. Two organs-on-a-chip

Author(s)

Tavares, R. S. N. ^[1] ; Tao, Thi Phuong ^[2] ; Maschmeyer, I ^[2] ; Maria-Engler, S. S. ^[3] ; Schaefer-Korting, M. ^[4] ; Winter, A. ^[2] ; Zoschke, C. ^[4] ; Lauster, R. ^[5] ; Marx, U. ^[2] ; Gaspar, L. R. ^[1]

Affiliation

^[1] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Av Cafe S-N, BR-14040903 Ribeirao Preto, SP - Brazil

^[2] TissUse GmbH, Oudenarder Str 16, D-13347 Berlin - Germany

^[3] Univ Sao Paulo, Sch Pharmaceut Sci, Clin & Toxicol Anal Dept, Av Prof Linea Prates 748, Cidade Univ, BR-05508000 Sao Paulo, SP - Brazil

^[4] Freie Univ, Inst Pharm Pharmacol & Toxicol, Konigin Luise Str 2 4, D-14195 Berlin - Germany

^[5] Tech Univ, Inst Biotechnol, Chair Med Biotechnol, Gustav Meyer Allee 25, D-13355 Berlin - Germany

• Document type: Journal article
• Source: International Journal of Pharmaceutics; v. 589, NOV 15 2020.
• Web of Science Citations: 0

Abstract

Skin model cultivation under static conditions limits the observation of the toxicity to this single organ. Biologyinspired microphysiological systems associating skin with a liver in the same circulating medium provide a more comprehensive insight into systemic substance toxicity; however, its advantages or limitations for topical substance toxicity remain unknown. Herein, we performed topical (OECD test guideline no. 439) and systemic administration of terbinafine in reconstructed human skin (RHS) vs. a RHS plus liver model cultured in TissUse' HUMIMIC Chip2 (Chip2). Aiming for a more detailed insight into the cutaneous substance irritancy/toxicity, we assessed more than the MIT cell viability: lactate dehydrogenase (LDH), lactate and glucose levels, as well as inherent gene expressions. Sodium dodecyl sulfate (SDS) was the topical irritant positive control. We confirmed SDS irritancy in both static RHS and Chip2 culture by the damage in the morphology, reduction in the lactate production and lower glucose consumption. In the static RHS, the SDS-treated tissues also released significantly high LDH (82%; p < 0.05) and significantly lower IL-6 release (p < 0.05), corroborating with the other metabolic levels. In both static RHS and Chip2 conditions, we confirmed absence of irritancy or systemic toxicity by LDH, glucose or lactate levels for topical 1% and 5% terbinafine and systemic 0.1% terbinafine treatment. However, topical 5% terbinafine treatment in the Chip2 upregulated IL-la in the RHS, unbalanced apoptotic and proliferative cell ratios in the liver and significantly increased its expression of CYP1A2 and 3A4 enzymes (p < 0.05), proving that it has passed the RHS barrier promoting a liver impact. Systemic 0.1% terbinafine treatment in the Chip2 increased RHS expression of EGFR, increased apoptotic cells in the liver, downregulated liver albumin expression and upregulated CYP2C9 significantly (p < 0.05), acting as an effective hepatotoxic terbinafine control. The combination of the RHS and liver model in the Chip2 allowed a more sensitive assessment of skin and hepatic effects caused by chemicals able to pass the skin (5% terbinafine and SDS) and after systemic 0.1% terbinafine application. The present study opens up a more complex approach based on the microphysiological system to assess more than a skin irritation process. (AU)

• FAPESP's process: 14/50928-2 - INCT 2014: Pharmaceutical Nanotechnology: a transdisciplinary approach
• Grantee: Maria Vitória Lopes Badra Bentley
• Support Opportunities: Research Projects - Thematic Grants