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Publication Number
US-11555821-B2
Publication Date
2023-01-17
Expiration Date
Abstract
The present disclosure relates to compounds that are useful as near-infrared fluorescence probes, wherein the compounds include i) a ligand that binds to the active site of carbonic anhydrase, ii) a dye molecule, and iii) a linker molecule that comprises an amino acid, amide, ureido, or polyethylene glycol derivative thereof. The disclosure further describes methods and compositions for making and using the compounds, methods incorporating the compounds, and kits incorporating the compounds.
Core Innovation
The invention provides CA IX-targeted near-infrared (NIR) fluorescence probes, salts, and related conjugates for optical imaging of cancer or inflammatory diseases. The compounds are described by a B-W-X-Y-Z formula in which B is a CA IX-targeted molecule, W comprises an extended hydrophobic residue, X comprises a hydrophobic spacer, Y comprises an amino acid spacer, and Z comprises an NIR dye.
After contracting tissue with the compound, illuminating with excitation light of a wavelength absorbed by the compound causes the compound to emit an optical signal in the tissue. The description emphasizes CA IX-targeted binding or selectivity together with fluorescence detection, and includes using the detected emitted signal to construct an image.
The disclosed compounds specify extended hydrophobic residues, hydrophobic spacers, amino acid spacers, and NIR dye components, with structural features that define the conjugation architecture. The imaging workflow may involve additional fluorescent compounds and image-guided surgery/resection contexts.
Claims Coverage
The independent claims cover two categories: a method of imaging cancer or inflammatory diseases using a CA IX-targeted B-W-X-Y-Z NIR fluorescence probe, and a composition comprising the selected probe compound together with at least one additional fluorescent compound. Across the independent claims, there are three inventive features.
Ca ix-targeted b-w-x-y-z imaging compound
A method of imaging cancer or inflammatory diseases by contracting tissue with a compound, or salt thereof, having the formula B-W-X-Y-Z, where B is a CA IX-targeted molecule, W comprises an extended hydrophobic residue, X comprises a hydrophobic spacer, Y comprises an amino acid spacer, and Z comprises a NIR dye.
Excitation and detection to image emitted optical signal
Illuminating the tissue with an excitation light of a wavelength absorbed by the compound and detecting the optical signal emitted by the compound in the tissue.
Composition with additional fluorescent compound
A composition comprising a compound selected from the group consisting of the CA IX-targeted compound(s) and at least one additional fluorescent compound.
Overall, the claim coverage centers on a CA IX-targeted B-W-X-Y-Z NIR fluorescence probe and an imaging workflow defined by excitation with absorbable light and detection of emitted optical signal in tissue; a further independent claim adds that the probe can be provided in a composition together with at least one additional fluorescent compound.
Stated Advantages
Deep tissue penetration.
Higher NIR fluorescence intensity, allowing lower dose.
Real-time visualization of tumor outlines and margins during biopsy/resection.
Improved contrast using single or multiple targeting constructs, including CA IX or alternative receptor ligands and distinguishable fluorophore colors.
Improved stability.
Improved tumor-to-background ratio.
Fast clearance/skin clearance.
Deeper tissue visualization.
Lower background autofluorescence.
Enabling detection of small/deep tumors.
Enabling use of lower dye doses.
Documented Applications
Image-guided surgery, including surgical excision/resection, with real-time visualization of tumor outlines/margins.
Optical diagnosis of cancer or inflammatory diseases using NIR fluorescence detection in tissue.
Biopsy-related imaging with visualization of tumor outlines/margins.
Optical detection in biological samples, including tumor microenvironment and hypoxic tissue targeting.
Metastatic disease detection.
Imaging using multiple targeting constructs, including CA IX and alternative receptor ligands with distinguishable fluorophore colors.
Optical imaging of CA IX-expressing tissues, tumors, and metastases using excitation light absorbed by a CA IX-targeted NIR fluorescence probe and detection of emitted fluorescence optical signals.
Use of emitted optical signal to construct an image.
Image-guided surgery/resection using fluorescent areas for surgical resection.
Diagnostic methods and kits.
Diagnosis using comparison to control datasets.
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