Optical Detection of Distal Lung Enzyme Activity in Human Inflammatory Lung Disease.

Autor:	Megia-Fernandez A; EaStCHEM, The University of Edinburgh School of Chemistry, Joseph Black Building, West Mains Road, Edinburgh, UK, EH9 3FJ., Marshall A; Translational Healthcare Technologies Group, Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh BioQuarter, Edinburgh, UK, EH16 4TJ., Akram AR; Translational Healthcare Technologies Group, Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh BioQuarter, Edinburgh, UK, EH16 4TJ., Mills B; Translational Healthcare Technologies Group, Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh BioQuarter, Edinburgh, UK, EH16 4TJ., Chankeshwara SV; EaStCHEM, The University of Edinburgh School of Chemistry, Joseph Black Building, West Mains Road, Edinburgh, UK, EH9 3FJ., Scholefield E; Translational Healthcare Technologies Group, Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh BioQuarter, Edinburgh, UK, EH16 4TJ., Miele A; Translational Healthcare Technologies Group, Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh BioQuarter, Edinburgh, UK, EH16 4TJ., McGorum BC; The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, UK, EH25 9RG., Michaels C; Translational Healthcare Technologies Group, Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh BioQuarter, Edinburgh, UK, EH16 4TJ., Knighton N; Department of Biomedical Engineering, University of Utah, 36 S Wasatch Dr, Salt Lake City, UT 84112, USA., Vercauteren T; School of Biomedical Engineering & Imaging Sciences, King's College London, London, UK, SE1 7EH., Lacombe F; Mauna Kea Technologies, 9, Rue d'Enghien, Paris, France75010., Dentan V; Mauna Kea Technologies, 9, Rue d'Enghien, Paris, France75010., Bruce AM; Translational Healthcare Technologies Group, Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh BioQuarter, Edinburgh, UK, EH16 4TJ., Mair J; Translational Healthcare Technologies Group, Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh BioQuarter, Edinburgh, UK, EH16 4TJ., Hitchcock R; Department of Biomedical Engineering, University of Utah, 36 S Wasatch Dr, Salt Lake City, UT 84112, USA., Hirani N; Translational Healthcare Technologies Group, Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh BioQuarter, Edinburgh, UK, EH16 4TJ., Haslett C; Translational Healthcare Technologies Group, Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh BioQuarter, Edinburgh, UK, EH16 4TJ., Bradley M; EaStCHEM, The University of Edinburgh School of Chemistry, Joseph Black Building, West Mains Road, Edinburgh, UK, EH9 3FJ., Dhaliwal K; Translational Healthcare Technologies Group, Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh BioQuarter, Edinburgh, UK, EH16 4TJ.
Jazyk:	angličtina
Zdroj:	BME frontiers [BME Front] 2021 Apr 07; Vol. 2021 (2021), pp. 9834163. Date of Electronic Publication: 2021 Apr 07 (Print Publication: 2021).
DOI:	10.34133/2021/9834163
Abstrakt:	Objective and Impact Statement. There is a need to develop platforms delineating inflammatory biology of the distal human lung. We describe a platform technology approach to detect in situ enzyme activity and observe drug inhibition in the distal human lung using a combination of matrix metalloproteinase (MMP) optical reporters, fibered confocal fluorescence microscopy (FCFM), and a bespoke delivery device. Introduction . The development of new therapeutic agents is hindered by the lack of in vivo in situ experimental methodologies that can rapidly evaluate the biological activity or drug-target engagement in patients. Methods . We optimised a novel highly quenched optical molecular reporter of enzyme activity (FIB One) and developed a translational pathway for in-human assessment. Results . We demonstrate the specificity for matrix metalloproteases (MMPs) 2, 9, and 13 and probe dequenching within physiological levels of MMPs and feasibility of imaging within whole lung models in preclinical settings. Subsequently, in a first-in-human exploratory experimental medicine study of patients with fibroproliferative lung disease, we demonstrate, through FCFM, the MMP activity in the alveolar space measured through FIB One fluorescence increase (with pharmacological inhibition). Conclusion . This translational in situ approach enables a new methodology to demonstrate active drug target effects of the distal lung and consequently may inform therapeutic drug development pathways. Competing Interests: KD, CH, and MB are shareholders of Edinburgh Molecular Imaging. MB, SVC, and AMF are inventors on a patent (WO 2016/151299 A1) held by the University Court of the University of Edinburgh that covers the probe and method of use. FL and VD are employees of Mauna Kea Technologies. TV owns stock from Mauna Kea Technologies. The other authors declare that they have no competing interests. (Copyright © 2021 Alicia Megia-Fernandez et al.)
Databáze:	MEDLINE
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