Award details

Combining fluorescence correlation spectroscopy with flow chambers and 3D cellular assemblies to observe macromolecular drugs delivery

Reference	BB/C505308/1
Principal Investigator / Supervisor	Dr Alain Pluen
Co-Investigators / Co-Supervisors	Dr David Berk, Dr Jeffrey Penny
Institution	The University of Manchester
Department	Manchester Pharmacy School
Funding type	Research
Value (£)	177,896
Status	Completed
Type	Research Grant
Start date	03/05/2005
End date	02/12/2008
Duration	43 months

Abstract

Novel therapies based on macromolecules have failed to fulfil their promises. This may be attributed to their inability to overcome physiological barriers such as extravasation, binding, uptake or intracellular trafficking, and to a lack of quantitative and systematic studies done on reliable models. The present project seeks to combine Fluorescence Correlation Spectroscopy (Zeiss Confocor 2) with a modified flow chamber incorporating 3D cellular assemblies in order to develop a reliable model to assess the delivery of drugs and novel medicines. The modified chamber incorporating 3D cellular assemblies will mimic a blood vessel and its surrounding tissue (endothelial cells, smooth muscle cells, fibroblasts...). Cells will be grown on both sides of an insert's membrane to form a 3D cellular assembly and provide a physiologically relevant system (convection will be possible by ensuring transport of fluid across the cells). The quantitative analysis of drug delivery will be done using Fluorescence Correlation Spectroscopy, technique able to determine diffusion constant, velocities or binding kinetics at very low concentrations of fluorescent macromolecules. The project comprises three aims: (1) Develop a flow chamber allowing the quantitative study of the delivery of small drugs and novel medicines i.e. develop the flow chamber and assess its optical properties, and develop the cell models, (2) Validate the FCS technology with measurements of fluorescent tracers in presence of flow and cell assemblies, i.e. evaluate the range of macromolecules to be used under flow condition and their concentration levels in order to measure diffusion, velocity and binding kinetics, and, (3) Assess the delivery of peptides targeted to specific receptors of endothelial cells under physiologically relevant conditions in vitro i.e. study the delivery of a potential medicine and its related kinetics. This project is multidisciplinary (biophysics, cell culture, pharmacokinetics, physical chemistry) and meets the Council's priorities for drug delivery (pharmacokinetics of novel medicines, intracellular trafficking, 3D cellular assemblies) and for animal experimentation's replacement.

Summary

unavailable

Committee	Closed Committee - Engineering & Biological Systems (EBS)
Research Topics	Pharmaceuticals, Technology and Methods Development, The 3 Rs (Replacement, Reduction and Refinement of animals in research)
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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