Drug risk assessment and repurposing using biomimetic chromatography and body-on-chip technology

Why did we fund this project?

This award aims to use body-on-a-chip technology to model plasma recirculation and test multiple organ toxicity on a single chip replacing some pharmacokinetic/pharmacodynamic (PK/PD) studies in rodents.

Over the last decade there has been interest from industry and regulatory bodies in the wider use of non-animal approaches to investigate how chemicals, including pharmaceuticals, interact with proteins and lipids in the body to predict whether they will be harmful to humans. Traditionally, this would be performed in vivo using PK/PD studies most commonly in rats and mice. The distribution of protein and lipids within the body can be mimicked in vitro using chromatography techniques to test the ability of the compound of interest to bind to these molecules. Biomimetic chromatography is a high-throughput technology and can help with ranking or screening drugs for unwanted physicochemical properties.

The student will collaborate with TissUse in Germany to couple biomimetic chromatography with organ-on-a-chip technology to create a platform with five organ-like components mimicking the heart, brain, lungs, kidneys and liver. Each component will contain human cells to enable multi-organ biodistribution and metabolism studies to be performed in a high-throughput platform. The student will then validate the platform using data from in vivo PET imaging studies and use the data to establish in silico models to predict drug distribution in those organs to aid with screening with novel compounds. The student will develop skills in 3D printing, chromatography, PET/CT imaging and cell culture techniques.

This award was made jointly with Unilever.

Drug discovery pipelines can be lengthy, expensive and prone to a high degree of attrition with few drug candidates successfully reaching the market. Animal testing has been amply used to select lead drug candidates for first-in-Man clinical studies.

Although the use of animals can be useful to assess drug distribution, metabolism and therapeutic effects, species differences versus humans often decrease the translational success rate of a new drug. Moreover, the use of animals at early stages of drug screening or during repurposing exercises can be expensive, can be impractical when handling large libraries of prospective drug candidates and can have low scientific value at the cost of a high number of animals used. Therefore, there is a need to design more efficient drug discovery pipelines and to increase confidence on selection of the lead compounds at early stages of the process.

This project will investigate the use of biomimetic chromatography as a fast, economic and high-throughput platform to screen and rank compounds' physicochemical properties, drug interaction with silence sites, and binding to human plasma proteins. In this project we will couple biomimetic chromatography with a modified body-on-chip technology to screen compounds' affinity to different human cell targets (to aid drug risk assessment and repurposing exercises), characterise multi-organ biodistribution and metabolism, and predict drug success in humans. Validation of the new methodology will be done by comparing it with gold-standard in vivo outcome measurements of the same drugs already tested in humans using micro-dosing Positron Emission Tomography (PET) imaging.

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PhD Studentship

Status

Active

Institution

University of Edinburgh

Grant reference number

NC/V001302/1

Award date

Jan 2021 - Jan 2024

Grant amount

£90,000 (Joint award with Unilever)