Compound Absorption in Polymer Devices Impairs the Translatability of Preclinical Safety Assessments

• Published in: Advanced healthcare materials 2024-04, Vol.13 (11), p.e2303561-n/a
• Main Authors: Kemas, Aurino M., Zandi Shafagh, Reza, Taebnia, Nayere, Michel, Maurice, Preiss, Lena, Hofmann, Ute, Lauschke, Volker M.
• Format: Article
• Language: English
• Subjects: Absorption; Absorptivity; Assessments; Chemical bonds; Devices; Dimethylpolysiloxanes - chemistry; Drug development; Drug Evaluation, Preclinical - methods; Hepatotoxicity; Human tissues; Humans; Hydrophobic and Hydrophilic Interactions; Hydrophobicity; Liver; Liver - drug effects; Liver - metabolism; logP; Medicin och hälsovetenskap; microphysiological system; Phenotypes; Physicochemical properties; Polydimethylsiloxane; Polymers; Polymers - chemistry; polymer‐drug interaction; Polytetrafluoroethylene; Polytetrafluoroethylene - chemistry; Safety; small molecule absorption
• ISSN: 2192-2640; 2192-2659; 2192-2659
• DOI: 10.1002/adhm.202303561

Organotypic and microphysiological systems (MPS) that can emulate the molecular phenotype and function of human tissues, such as liver, are increasingly used in preclinical drug development. However, despite their improved predictivity, drug development success rates have remained low with most compounds failing in clinical phases despite promising preclinical data. Here, it is tested whether absorption of small molecules to polymers commonly used for MPS fabrication can impact preclinical pharmacological and toxicological assessments and contribute to the high clinical failure rates. To this end, identical devices are fabricated from eight different MPS polymers and absorption of prototypic compounds with different physicochemical properties are analyzed. It is found that overall absorption is primarily driven by compound hydrophobicity and the number of rotatable bonds. However, absorption can differ by >1000‐fold between polymers with polydimethyl siloxane (PDMS) being most absorptive, whereas polytetrafluoroethylene (PTFE) and thiol‐ene epoxy (TEE) absorbed the least. Strikingly, organotypic primary human liver cultures successfully flagged hydrophobic hepatotoxins in lowly absorbing TEE devices at therapeutically relevant concentrations, whereas isogenic cultures in PDMS devices are resistant, resulting in false negative safety signals. Combined, these results can guide the selection of MPS materials and facilitate the development of preclinical assays with improved translatability. Identical microdevices are fabricated from eight different polymers and it is found that absorption of prototypic compounds with different physicochemical properties differs by >1000‐fold between materials. Using 3D human liver cultures, it is shown that minimizing absorption can improve the accuracy of pharmacological or toxicological testing. These results have important implications for improving preclinical assay accuracy in drug development.