Near-Infrared Cyanine Dye Conjugates With Low Albumin Binding
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Solution Overview
Problem
Existing near-infrared dyes for biomedical imaging face challenges with optimal solubility, low aggregation in aqueous media, high fluorescence efficiency, and suboptimal biological properties, particularly when conjugated to biomolecules targeting pathologic tissues like tumors, leading to non-specific accumulation and reduced diagnostic efficacy.
Innovation Solution
Development of cyanine dyes with low binding affinity for human albumin, enabling efficient extravasation and specific targeting through conjugation with suitable moieties, enhancing diagnostic accuracy and sensitivity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Temperature
If near-infrared dyes are used for biomedical imaging, then penetration depth is improved, but non-specific accumulation and false positives occur
Solution Approach 1:
The patent modifies the chemical structure of cyanine dyes by introducing specific substituents (e.g., sulfonate groups, heterocyclic moieties) to alter their binding affinity parameters. This changes the physiological behavior of the dye, reducing non-specific protein binding while maintaining near-infrared emission properties for deep tissue penetration.
Solution Approach 2:
The invention creates composite dye molecules combining the cyanine chromophore with specific functional groups (sulfonate, heterocyclic rings) that provide both the desired optical properties and improved biological compatibility. This composite structure achieves both deep penetration and reduced false positives.
2Stability of the object's composition
If dyes with high binding affinity to plasma proteins are used, then stability in plasma is improved, but tissue extravasation rate decreases
Solution Approach 1:
The patent adjusts the hydrophilicity and charge parameters of the dye molecules by introducing sulfonate groups and heterocyclic substituents. This modification creates an optimal balance where the dye maintains sufficient plasma stability without excessive protein binding, enabling adequate tissue extravasation for diagnostic imaging.
3Measurement precision
If cyanine dyes are conjugated to tumor-targeting moieties, then sensitivity and specificity are improved, but complexity of conjugate preparation increases
Solution Approach 1:
The patent incorporates pre-installed reactive functional groups (carboxylic acids, amines, heterocyclic moieties) directly into the cyanine dye structure during synthesis. This preliminary preparation enables straightforward conjugation with targeting moieties via standard chemistries, reducing the overall complexity of conjugate preparation while maintaining high sensitivity and specificity.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The new cyanine dyes provide improved solubility and specificity for molecular imaging, allowing precise detection of pathologic tissues by reducing plasma sequestration and increasing the free fraction available for interaction with molecular targets.
Implementation Method 1
Dyes are chemical entities that absorb photons of a specific wavelength upon light excitation and re-emit some of that energy, depending on quantum efficiency, usually at a longer wavelength. Particularly, cyanine dyes are fluorescent organic molecules characterized by a delocalized electron system
Implementation Method 2
cyanine dyes are fluorescent organic molecules characterized by a delocalized electron system that spans over a polymethine bridge and is confined between two nitrogen atoms
Implementation Method 3
ICG is routinely used to assess tissue perfusion and for angiographic applications due to the strong binding to plasma protein (blood pool effect)
Implementation Method 4
ICG distributes and accumulates in tumor tissues by a combination of passive diffusion and enhanced permeability and retention (EPR) effect
Data Source
AI summary
The present invention relates to the field of optical imaging. More particularly, it relates to compounds of the cyanine family with near- infrared emission characterized by improved physico-chemical and biological properties and to conjugates with biological ligands thereof. The invention also relates to the use of these compounds as optical diagnostic agents in imaging or therapy of solid tumors, to the methods for their preparation and to the compositions comprising them. The compounds have formula (I), formula (I), wherein X is direct bond or -O-; Y is a group selected from linear or branched C1-C6 alkyl, C3-C7 cycloalkyl and heterocyclyl, substituted by at least two hydroxyl groups; R1 and R2 are each independently a linear or branched C1-C6 alkyl substituted by a group selected from -SO3H, -COOH, -CONH2 and - COO-C1-C6 alkyl; and R3 is hydrogen, -SO3H or a linear or branched C1-C6 alkyl substituted by -COOH or -CONH-Y, wherein Y is a group selected from linear or branched C1-C6 alkyl, C3-C7 cycloalkyl and heterocyclyl, substituted by at least two hydroxyl groups.