Water soluble novel cyanine fluorophore with tunable properties between near IR and SWIR region for in vivo imaging
Inventors
Schnermann, Martin J. • Bandi, Venu G.
Assignees
US Department of Health and Human Services
Publication Number
US-11465993-B2
Publication Date
2022-10-11
Expiration Date
2039-08-23
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Abstract
Cyanine fluorophores including a nine-carbon polymethine bridge are disclosed. The cyanine fluorophores have absorbance and/or emission maxima in the near-infrared (NIR) and short-wave infrared (SWIR) wavelength ranges. Methods of making and using the cyanine fluorophores are also disclosed. The compounds are useful in fluorescence imaging, more particularly in cancer treatment. The compounds have generic formula (I):
Core Innovation
The invention discloses cyanine fluorophores that include a nine-carbon polymethine bridge, with absorbance and/or emission maxima in the near-infrared (NIR) and short-wave infrared (SWIR) wavelength ranges. These fluorophores have a generic chemical structure according to Formula I, with various substituents enabling tunable properties, such as solubility and conjugation to targeting agents or drugs. The invention also includes methods of making and using these cyanine fluorophores, which can be conjugated to antibodies or other targeting moieties for applications like fluorescence imaging.
The problem being addressed arises from the limitations of existing fluorescence imaging tools in medical applications, especially cancer treatment. Current surgical techniques relying on NIR light suffer from limited image resolution and tissue penetration due to light scattering, restricting fluorescence imaging effectiveness. Studies in the SWIR region that could improve spatial resolution and tissue penetration have relied on materials with safety concerns that hinder translation into in vivo settings. Additionally, commercially available NIR dyes have emission maxima only up to 800 nm, creating a need for bathochromic shifted dyes extending fluorescence into the NIR and SWIR ranges with suitable aqueous solubility, reduced toxicity, and conjugation capabilities for diagnostic and therapeutic purposes.
Claims Coverage
The claims include one independent claim concerning a compound according to Formula I and methods of using such compounds. Five main inventive features are disclosed, covering chemical structure modifications, functional group variations, conjugation features, pharmaceutical composition inclusion, and imaging methods.
Compound having a chemical structure according to Formula I with specific substituents
The claimed compound has a chemical structure according to Formula I or stereoisomers or pharmaceutically acceptable salts thereof, with specific features including (i) positions R3 and R6 being sulfonate groups, (ii) the other R groups being H or defined substituents, (iii) R9 and R10 being alkyl sulfonate, alkyl, or polyethylene glycol-based groups, (iv) Y1 and Y2 being selected atoms or substituted carbons including possible conjugatable moieties, targeting agents, or drugs, and (v) R11 and R12 forming a fused ring system in some embodiments.
Structural variations in the fused ring system and substituents
Compounds may have structures according to Formula II-V with variations where Z1 and Z2 independently are O, S, or N-substituted, X1-X4 atoms or groups vary as carbons or oxygen with substituents including conjugatable moieties, targeting agents, or drugs. Substitutions include sulfonate, aminoalkyl, alkyl, and trityl groups. The substituents may enable conjugation to other molecules or drugs.
Inclusion of conjugatable moieties, targeting agents, or drugs
At least one of the substituents R1-R8, R13, or the groups Y1 and Y2 may include a conjugatable moiety, targeting agent such as an antibody, or a drug. This facilitates coupling the fluorophore to biomolecules or therapeutic agents, enabling targeted imaging or drug delivery applications.
Pharmaceutical composition comprising the compound
Pharmaceutical compositions comprising a compound according to Formula I and a pharmaceutically acceptable carrier are claimed, enabling administration of the fluorophores in suitable formulations for medical or research applications.
Method of using the compound for fluorescence imaging
Methods include combining the compound with a sample and visualizing the compound by irradiating the sample with light in the near-infrared or short-wave infrared range to produce fluorescence, detecting the emitted fluorescence. Additional features include targeting agents binding to specific targets in the sample, administration to a subject, and imaging target areas such as tumors in vivo, including subsequent excision guided by fluorescence.
The claims comprehensively cover cyanine fluorophores with tunable substituents enabling NIR/SWIR fluorescence, conjugation capabilities, pharmaceutical formulations, and methods of fluorescence imaging in biological samples and subjects, especially for cancer applications.
Stated Advantages
Improved spatial resolution and tissue penetration compared to traditional NIR fluorophores due to absorption and emission maxima extended into the SWIR region.
Nontoxic, aqueous-soluble, and non-aggregating cyanine fluorophores suitable for in vivo applications.
Capability for conjugation to targeting agents such as antibodies or drugs, enabling targeted imaging and therapeutic delivery.
Fluorophores provide absorbance maximum wavelengths ≥650 nm with high molar absorptivity (up to 300,000 M−1cm−1) for sensitive detection.
Documented Applications
Fluorescence imaging in medical fields, particularly cancer treatment and fluorescence-guided surgery.
Live-cell localization and tracking, including intracellular component imaging using targeted fluorophores.
In vitro, ex vivo, and in vivo localization and tracking of targets in biological samples, tissues, and living subjects.
Visualization of tumors by administration of fluorophore compounds with targeting agents and detection of fluorescence during surgery or diagnosis.
Drug delivery and targeted drug delivery, combining fluorophores with therapeutic agents to track distribution and localization.
Use in various fluorescence microscopy techniques including single-molecule localization microscopy (SMLM), PALM, STORM, dSTORM, biplane imaging, TRABI, and FRET.
Vascular structure visualization in vivo at high resolution.
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