Connected In Vitro Tissue Models for Oral Drug Delivery

Morten Leth Jepsen

Research output: Book/ReportPh.D. thesisResearch

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Abstract

Oral drug delivery is the preferred drug administration route, however, many oral drugs are rejected during in vivo studies. Before an oral drug reaches the systemic circulation, it is exposed to first pass metabolism which reduces the amount of active drug reaching its target. The first pass metabolism is a combination of the gastrointestinal tract which absorbs the drug into the blood vessels which transport the drug to the liver which metabolizes the drug. In drug discovery, good prediction of the first pass metabolism can help to select the best oral drugs and formulations for the subsequent in vivo studies.
To predict the first pass metabolism, three in vitro cell-based tissue models have been developed throughout this PhD project. The cells are grown on or in soft hydrogel growth-matrices in 3D-printed inserts which are compatible with commercial titer plates. To secure in vivo-like growth matrices, a method for measuring hydrogel stiffness has been developed and employed to characterize the hydrogel growth-matrices. The Caco-2 cell line, HUVEC cells, and the HepG2 cell line are used in this project to simulate the small intestinal tissue, the vascular tissue and the liver tissue, respectively. The 3D-printed inserts with each their tissue model can easily be connected by assembling the inserts on top of each other. This allows for investigation of interactions between the tissues.
The Caco-2 small intestinal tissue model displays drug permeabilities comparable to what is previously seen for this cell line. However, the electrical resistance is closer to that found in vivo then other Caco-2 based models. The HUVEC vascular endothelial tissue model only serves as a diffusional barrier. This tissue model can in the future be improved by addition of shear stress to gain in vivo-like flow resembling the bloodstream. The HepG2 liver tissue model grows as spheroids in 3D giving the hepatic cells gradients of nutrients resembling the in vivo liver tissue.
In conclusion, this PhD project covers an in vitro method for predicting the first pass metabolism of drugs. Potentially, this method can increase the success rate of in vivo studies and reduce drug development costs.
Original languageEnglish
PublisherDTU Health Technology
Number of pages150
Publication statusPublished - 2019

Projects

Drug transport in in vitro intestine models

Jepsen, M. L., Dufva, M., Boisen, A., Nielsen, L. H., Lind, J. U., Hedhammar, M. & Steffansen, B.

Grundforskningsfonden

15/12/201612/03/2020

Project: PhD

Cite this

Jepsen, M. L. (2019). Connected In Vitro Tissue Models for Oral Drug Delivery. DTU Health Technology.