CA-IX NIR Fluorescent Probes With Low Non-Specific Accumulation
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Solution Overview
Problem
Current fluorescent probes targeting Carbonic Anhydrase IX (CA-IX) for biomedical imaging suffer from issues such as high non-specific accumulation, low specificity, and instability in vivo, limiting their effectiveness in diagnosing and treating hypoxic tumors.
Innovation Solution
Development of heptamethine cyanine dyes conjugated to an acetazolamide moiety at a different position of the scaffold, specifically at position 1 of an indolenine ring, which enhances stability and affinity for CA-IX, reducing non-specific interactions and improving bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If conventional fluorescent probes (ICG, Fluorescein) are used for tumor imaging, then passive diffusion and EPR effect enable tumor accumulation, but high mass doses (>1 mg/kg) are required and false positive/negative responses occur
Solution Approach 1:
The patent introduces a targeting moiety (such as RGD peptide, TAT peptide, or antibody fragment) as an intermediary between the fluorescent dye and the tumor tissue. This mediator specifically binds to receptors overexpressed on tumor cells (e.g., integrins, transferrin receptors), enabling targeted accumulation at much lower doses while improving detection accuracy through specific binding interactions.
Solution Approach 2:
The patent creates composite fluorescent probes by conjugating fluorescent dyes (e.g., cyanine dyes, fluorescein derivatives) with targeting moieties (peptides, antibodies, aptamers). This composite structure combines the optical properties of the dye with the specific binding capability of the targeting moiety, achieving both low-dose administration and high detection precision simultaneously.
2Measurement precision
If dye-biomolecule conjugates are used to improve sensitivity and specificity, then tumor selective properties are enhanced, but in vivo behavior is strongly affected by biological properties of the fluorescent moiety
Solution Approach 1:
The patent optimizes the structural parameters of the fluorescent moiety, specifically using dyes with emission wavelengths in the near-infrared region (700-900 nm). This parameter change reduces interaction with biological tissues, minimizes autofluorescence interference, and improves photostability in vivo, thereby maintaining both sensitivity and reliability.
Solution Approach 2:
The patent introduces stable linker molecules (such as PEG linkers, amide bonds, or disulfide bonds) as intermediaries between the dye and targeting moiety. These linkers are designed to be metabolically stable or conditionally cleavable, maintaining the integrity of the conjugate in circulation while allowing controlled release or activation at the target site, thus preserving in vivo stability.
3Length of stationary object
If cyanine dyes are used for NIR imaging, then penetration depth is improved compared to visible dyes, but non-specific accumulation and low selectivity limit effectiveness
Solution Approach 1:
The patent attaches targeting moieties (such as RGD peptides targeting integrins, or antibody fragments targeting specific surface markers) to the cyanine dye. This intermediary enables specific binding to tumor cells while the cyanine core maintains its deep tissue penetration capability, achieving both long penetration depth and high tissue selectivity.
Solution Approach 2:
The patent modifies the cyanine dye structure by introducing polar groups (such as sulfonate groups) at specific positions to enhance water solubility and reduce non-specific binding to plasma proteins and normal tissues. This local modification improves selectivity without compromising the overall NIR penetration depth of the dye.
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 probes exhibit high selectivity for CA-IX-expressing cells, low plasma protein binding, and improved imaging efficacy with a high signal-to-noise ratio, suitable for molecular imaging at low doses.
Implementation Method 1
fluorescent probes able to efficiently target Carbonic Anhydrase IX enzyme (CA-IX) and comprising heptamethine cyanine dyes with near-infrared (NIR) emission
Implementation Method 2
Dyes are chemical entities that absorb photons of a specific wavelength upon light excitation and re-emit some of that energy
Implementation Method 3
CA-IX is a homo-dimeric glycoprotein located on the cell surface and is a member of the large carbonic anhydrases (CAs) family of zinc metalloenzymes
Data Source
AI summary
The present invention relates to the field of optical imaging. More particularly, it relates to fluorescent probes targeting carbonic anhydrase nine (CA-IX) comprising near-infrared (NIR) dyes of the cyanine. The invention also relates to the methods for preparing these compounds, to pharmaceutical compositions and kits incorporating them and to methods of use them as optical diagnostic agents in imaging or therapy of diseases such as solid tumors with hypoxic tissues involving cells expressing CA-IX.