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Organisation:

UniServices

Contact:

Adam Podmore

Click Chemistry

The presence of hypoxia, oxygen concentrations below normal physiological levels, is a pathophysiological condition found in tumours, ischemic tissue (cardiac ischemia, brain ischemia, etc.), inflamed tissue (e.g. rheumatoid arthritis), and vascular disease (e.g. diabetes). Given this, there is great interest in methods for the detection and imaging of hypoxia, particularly for research purposes. Analogues of validated hypoxia markers such as pimonidazole and EF5, bearing an azide or a terminal alkyne have been synthesised. These have been demonstrated to undergo a copper (I)-catalysed azide-alkyne 1,3-dipolar cycloaddition, referred to as ‘click chemistry’, with suitable probes. Preferred probes are fluorescent or fluorogenic molecules bearing a terminal alkyne or azide, respectively. This enables very sensitive and highly selective detection of hypoxic cells.

Objective

UniServices is seeking investment and partnerships with industry.

Unique Selling Propositions

  • Click chemistry reaction is much faster than antibody-based methods (typical procedure 30 min rather than overnight)
  • Does not require cell fixation, permeabilisation, or antigen retrieval and thus avoids all problems and pitfalls associated with these extra sample processing steps
  • Compatible with other antibody-based methods
  • Bond between terminal alkyne and azide is covalent and irreversible while association between antibody and antigen is reversible
  • Click chemistry-based method can be performed on whole-mount (thick) tissue sections, giving 3D information on tissue hypoxia, in contrast to antibody-based methods that generally only work on thin tissue sections (due to small molecules involved that diffuse much faster than antibodies)
  • Click chemistry-based method is at least as sensitive as antibody-based methods
  • Versatility allows easy selection of optimal pair of hypoxia marker plus probe
  • Wide range of hypoxia markers and fluorescent probes available. Fluorescent probes of any desired wavelength can be easily generated
  • Compatible with other techniques such as Western blotting (no need for fixation & permeabilisation)
  • Azide and terminal alkyne functionalities are 'bio-orthogonal'

Applications

  • Quantitation of hypoxic cells by flow cytometry
  • Sorting of hypoxic and oxic cells by fluorescence-activated cell sorting
  • The technology is suitable in ex vivo (e.g. tumours) or in vitro settings
  • Imaging of hypoxia in tissue sections by fluorescence microscopy

Project Status

Proof of Concept - Early prototype built

IP Strategy

PCT application "agents and methods for detection and/or imaging of hypoxia" published on 24 November 2011 (WO 2011/145957 A1).

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