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and disease biology requires a model that mimics all the complexity of the heart. The model is still in development, but there is hope that it will be useable as an ex-vivo translational model for drug discovery and understanding cardiac disease.
3D bioprinting 3D bioprinting involves printing-like techniques, where ‘ink’, often silicon, printed on to a gelatin/fibrogen matrix is used to build scaffolds that are populated with cells during or after the printing process to create biological structures. These can include organ components in which the heterogeneity and architecture of their biological counterparts are preserved, providing a more translatable system than 2D models. This has been of use in the kidney field, where
previously there has been a lack of translatable models. We have been collaborating with a group at Harvard University who have published a bioprint- ing method for creating 3D human renal proximal tubules9. This provides a realistic model for study- ing cellular crosstalk, drug uptake, delivery and toxicity, and to support biomarker discovery, target identification and validation. The aim for the future will be to build on the complexity of these models to mimic the in vivo environment. Other structures, such as vasculature, could be printed and linked to simulate cellular crosstalk, and eventually compo- nents of a whole kidney could be created. An imme- diate next step is to use patient-derived IPS cells in place of cell lines to mimic real patients’ disease. As with other human tissue-based models, 3D-bio- printed systems can be used to understand complex,
Drug Discovery World Summer 2018
system-wide interactions and simulate the disease mechanisms and compound behaviour early in the drug discovery process.
Mass-spectrometry imaging (MSI) MSI combines mass spectrometry data with spa- tial information to map the molecular composi- tion of a sample surface in exquisite detail. MSI can show distribution and behaviour of almost all molecule types in a sample. This includes drug candidates and their metabolites, as well as pro- teins and lipids. This depth of information pro- vides unparalleled insights into how drugs and tar- gets interact in a tissue. It can be used to give pre- dictive information on compound safety and effi- cacy, as well as guiding drug delivery methods and formulations. The predominant use of MSI at AstraZeneca is
in early discovery projects to inform preclinical decision making. A key area for us where this has had significant impact is in understanding blood- brain barrier (BBB) penetration. Due to the com- plexity of systems, this is a challenge to model and a ‘blind spot’ in terms of predicting compound behaviour. In a recent publication, we demonstrat- ed that MSI could be used to show how drug-drug interactions influence blood-brain barrier perme- ability. Traditional imaging technology would not be able to show these interactions in all their com- plexity, so MSI bridges this gap10. A joint project between AstraZeneca and Cancer
Research UK (CRUK) aims to map cancer topolo- gy in unprecedented molecular detail to help in PK/PD modelling, determining phenotypes and
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