To date, methods employed for drug development and pre-clinical assessment are primarily based on physicochemical parameters such as proteomics, NMR, spectroscopy, calorimetry and ELISA. These traditional drug profiling approaches, although capable of delivering biophysical attributes, do not currently include high resolution 3D observation of either drug delivery vesicles or drug-induced cellular responses.
This project aims to develop a high-throughput correlative 3D imaging process for biomaterials and recipient cells to better understand the action of pharmaceutivals within and across cell populations. This will become the basis of a new pre-clinical testing method and provide a tool for industrial partners to further validate drug suitability during research and development. We will use established sample preparation protocols (including snap freezing to preserve native structures at physiologically relevant conformations) and refine them further using model mammalian cell lines (Vero, A549, HeLa and RPE-1) to ensure consistent imaging within cell populations. These will then be exposed to selected drugs including (a) vaccine-grade activirosomes (existing collaboration), (b) cell division disruptors and (c) antivirals. We will then seek to refine time points for sample harvest that allow us to assess the effects of these drugs on cellular ultrastructure (cell size and gross morphology, polarization of cytoskeleton and endosomal factors, change in size and distribution of organelles, nuclear membrane remodelling and exosome production). Effects will be captured through the use of our existing correlative cryo-imaging platform at beamline B24 and their potency as indicators of drug-induced side-effects will be evaluated. We aim to deliver a package of refined protocols ranging from sample preparation to data collection and processing along a preliminary catalogue of cellular features that we can assess to delineate suitability of pharmaceuticals prior to further studies.
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