Zwitterionic Disease-Targeted NIR Imaging Agents for Low Background
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Solution Overview
Problem
Existing near-infrared (NIR) fluorescence imaging agents suffer from low target-to-background ratio (TBR) due to non-specific uptake in normal tissues and rapid metabolism, necessitating improved fluorophores with enhanced tumor targeting and stability for better imaging accuracy.
Innovation Solution
Incorporation of antigen-specific targeting vectors into zwitterionic fluorophores balances charge, enhancing biodistribution and clearance while increasing specific uptake, thereby improving the target-to-background ratio.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If known fluorophores are used for NIR imaging, then imaging capability is provided, but they clear through the liver resulting in undesirable fluorescence throughout the gastrointestinal tract and low target-to-background ratio
Solution Approach 1:
The patent modifies the chemical structure of fluorophores by incorporating zwitterionic groups with specific charge-balancing moieties, changing the physicochemical parameters to achieve renal clearance instead of hepatic clearance, thereby eliminating gastrointestinal background fluorescence and improving target-to-background ratio
Solution Approach 2:
The patent creates composite fluorophore structures combining zwitterionic groups with targeting vectors, merging the benefits of charge-balanced renal clearance with specific antigen targeting capability to simultaneously improve biodistribution and target specificity
2Measurement precision
If advanced fluorophores are developed to lower non-specific uptake, then target-to-background ratio improves, but they become metabolized in minutes to hours reducing stability
Solution Approach 1:
The patent changes the metabolic stability parameter by incorporating zwitterionic groups that resist enzymatic degradation, allowing the fluorophores to maintain stability in blood circulation while still achieving low non-specific uptake through renal clearance mechanisms
Solution Approach 2:
The patent ensures continuous circulation of the fluorophore by designing structures that resist metabolism and degradation, maintaining stable blood levels throughout the imaging period to enable prolonged observation and improved imaging accuracy
3Measurement precision
If fluorophores are designed for rapid clearance, then background fluorescence is reduced, but circulation time is shortened reducing imaging window
Solution Approach 1:
The patent optimizes the molecular weight and charge characteristics of zwitterionic fluorophores to achieve ideal renal filtration properties, ensuring rapid clearance from blood to reduce background while maintaining sufficient circulation time for complete target uptake and imaging
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 charge-balanced zwitterionic fluorophores provide superior optical imaging properties with higher resolution and stability, reducing non-specific binding and prolonging circulation time for enhanced imaging accuracy.
Implementation Method 1
the inclusion of the targeting ligand increases the time of circulation and prevents additional degradation after binding to target cells. These in vivo properties help improve the target-to-background ratio of imaged tissues
Implementation Method 2
Near infrared (NIR) fluorescence has potential importance in the medical field, particularly in diagnostics and image-guided surgery
Implementation Method 3
targeting vectors directed to prostate-specific membrane antigen (PSMA), bombesin receptors, somatostatin receptors, fibroblast activation protein (FAP) would provide fluorophores with increased signal for more accurate imaging
Data Source
AI summary
The invention is based, at least in part, on the discovery that replacement of a key bond in the near-infrared fluorophore with a carbon-carbon bond conjugation to a targeting ligand results in vastly increased stability as compared to NIR fluorophores without such a bond, while preserving ligand and zwitterionic properties. In at least one aspect, the invention provides an imaging agent dye comprising a charge-balanced imaging agent conjugated to a targeting vector, wherein the targeting vector is a PSMA binding vector, such as dPSMA-617 or KUE, a FAP binding vector, a bombesin receptor binding vector, or a somatostatin receptor binding vector, and the charge-balanced imaging agent is ZW-800-1, ZW-830-1, or ZW-700-1-Forte.