Iridium Phosphorescent Reagent for Real-Time Tissue Oxygen Mapping
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Solution Overview
Problem
Existing methods for measuring oxygen concentration in cells and tissues are invasive, lack real-time capability, or require long metabolic times, and existing reagents have short phosphorescence lifetimes, making it difficult to distinguish between normal and hypoxic tissues.
Innovation Solution
Development of iridium complexes with coumarin 6 or coumarin 545T as aromatic ligands and dialkylethylenediamine as ancillary ligands, which exhibit phosphorescence lifetimes of not less than 30 μs in the red region, enabling imaging and quantification of oxygen concentration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If a microelectrode is inserted into the tissue to measure the oxygen concentration, then the oxygen partial pressure can be measured at a specific position, but the method is invasive and only allows measurement near the electrode
Solution Approach 1:
The patent replaces the mechanical microelectrode insertion method with a chemical/optical sensing approach. The iridium complex acts as a chemical probe that emits phosphorescence signals in response to oxygen concentration, eliminating the need for physical electrode insertion into tissues while maintaining measurement capability.
Solution Approach 2:
The iridium complex serves as an intermediary substance that mediates between the oxygen molecules in tissues and the detection system. The complex interacts with oxygen through quenching of phosphorescence, converting chemical information into optical signals that can be detected non-invasively.
2Object-affected harmful factors
If the ESR signal of a paramagnetic probe molecule is used to measure oxygen concentration, then the measurement can be performed without insertion, but real-time measurement is incapable
Solution Approach 1:
The patent utilizes the phosphorescence emission process, which occurs on a microsecond timescale, to achieve real-time measurement. The phosphorescence lifetime of the iridium complex provides a temporal window for detecting oxygen concentration changes dynamically, enabling real-time monitoring without mechanical insertion.
3Measurement precision
If a nitroimidazole-based probe molecule is used, then the oxygen concentration can be measured in hypoxic cells, but the metabolism of the agent requires a long time and data can only be obtained several hours after administration
Solution Approach 1:
The patent replaces the metabolic trapping mechanism of nitroimidazole with a direct phosphorescence quenching mechanism. The iridium complex directly senses oxygen concentration through phosphorescence lifetime changes without requiring cellular metabolism or enzymatic processing, eliminating the several-hour delay associated with nitroimidazole metabolism.
4Object-affected harmful factors
If water-soluble porphyrin or ruthenium complex is used for luminescence measurement, then the oxygen partial pressure in tissue can be non-invasively visualized, but the data are limited to blood oxygen levels only
Solution Approach 1:
The patent modifies the key parameter of phosphorescence lifetime to extend the measurement capability beyond blood oxygen levels. The iridium complex exhibits phosphorescence lifetime in the microsecond range that is sensitive to oxygen concentrations found in both blood and solid tissues, enabling versatile measurement across different tissue types and oxygenation states.
5Illumination intensity
If BTPHSA iridium complex is used, then phosphorescence imaging can be performed in the near-infrared region, but the phosphorescence lifetime is as short as 2.0 μs and oxygen responsiveness is low making it difficult to distinguish between normal and hypoxic tissues
Solution Approach 1:
The patent optimizes the phosphorescence lifetime parameter by selecting specific ligands (coumarin 6 or coumarin 545T with dialkylethylenediamine) that extend the lifetime to at least 30 μs. This parameter change enhances oxygen responsiveness while maintaining red region emission, enabling clear distinction between normal and hypoxic tissues through lifetime measurements.
6Measurement precision
If PPZ4DMMD and PPZ3DMMD iridium complexes are used, then phosphorescence lifetime is extended to 18 μs with higher oxygen responsiveness, but the phosphorescence lifetime has not reached the required lifetime for measurement using a commercially available microplate reader
Solution Approach 1:
The patent further extends the phosphorescence lifetime parameter by optimizing the ligand structure to achieve at least 30 μs lifetime. This parameter change ensures compatibility with commercially available microplate readers while maintaining high oxygen responsiveness, enabling both in vitro and in vivo applications.
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 iridium complexes allow for non-invasive, real-time imaging and quantification of oxygen concentration in cells and tissues, with enhanced phosphorescence lifetimes suitable for use in microplate readers and in vivo imaging, facilitating the detection of hypoxic cells and tissues.
Implementation Method 1
the inventors developed an iridium complex which has a phosphorescence lifetime of not less than 30 μs in the red region
Implementation Method 2
the oxygen concentration is measured based on the fact that the phosphorescence lifetimes of water-soluble porphyrin derivatives and ruthenium complexes change (due to quenching) depending on the blood oxygen level
Data Source
AI summary
The present invention aims to develop a compound and a reagent having long phosphorescence lifetimes, for use in imaging of a hypoxic cell/tissue or for use in measurement/quantification of the oxygen concentration thereof. The present invention provides a reagent for measuring oxygen concentration, comprising a compound represented by the following General Formula (I) or (II).wherein R1 and R2 each independently represent hydrogen or a C1-C6 hydrocarbon group; and X− represents a counter anion.