Bioreductive Hypoxia Markers With Click Mapping for Tumor Imaging
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Solution Overview
Problem
Hypoxic solid tumors are resistant to radiotherapy and chemotherapy due to impaired drug delivery and oxygen depletion, posing a significant challenge to therapeutic interventions and leading to poor local control and overall survival.
Innovation Solution
Development of bioreductively-activated compounds, such as nitroimidazoles, benzotriazene-1,4-dioxides, and substituted 1,2,3/1,2,4-triazoles, conjugated with fluorescent or radioactive moieties, which selectively target and image hypoxic cells through click chemistry, enabling precise hypoxia mapping and therapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional radiotherapy and chemotherapy are used to treat solid tumors, then treatment can be administered, but the therapy is ineffective due to tumor hypoxia and impaired drug delivery
Solution Approach 1:
The patent uses hypoxia-activated prodrugs as intermediaries that convert inactive compounds into active therapeutic agents specifically within hypoxic tumor regions. The prodrugs remain stable during delivery and only activate when encountering hypoxic conditions, thereby overcoming the resistance to conventional therapies while maintaining selective efficacy in the target tissue.
Solution Approach 2:
The invention exploits the parameter change of oxygen concentration to trigger therapeutic activation. By designing compounds with oxygen-sensitive chemical bonds or groups that break or transform under hypoxic conditions, the therapy transitions from inactive to active state specifically in hypoxic tumor regions, bypassing the resistance mechanism while preserving normal tissue safety.
2Measurement precision
If hypoxia-activated compounds are used to target hypoxic cells, then therapeutic precision is improved, but drug delivery to hypoxic regions remains impaired
Solution Approach 1:
The hypoxia-activated prodrugs utilize the hypoxic environment itself as the activation trigger, requiring no external activation system or complex delivery mechanism. The compounds are passively delivered to tumor regions and automatically activate in response to the hypoxic conditions they encounter, thereby achieving both precision targeting and adequate delivery through the same molecular design.
3Measurement precision
If bioreductively-activated compounds are administered, then hypoxia imaging and mapping accuracy is improved, but the complexity of the therapeutic system increases
Solution Approach 1:
The patent designs compounds that simultaneously serve multiple functions: they act as both imaging agents for hypoxia mapping and as prodrugs for therapeutic activation. This multi-functionality eliminates the need for separate diagnostic and therapeutic systems, thereby improving hypoxia mapping accuracy while avoiding the complexity of integrated multi-component systems.
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
These compounds provide accurate hypoxia imaging and therapy by selectively binding to hypoxic cells, enhancing radiotherapy and chemotherapy sensitivity, thereby shrinking tumors and reducing hypoxic regions.
Implementation Method 1
BA is a bioreductively-activated moiety/nuclei, e.g., nitroimidazoles, benzotriazene-1,4-dioxides e.g., tirapazamine, and analogs thereof
Implementation Method 2
conjugated with fluorescent or radioactive moieties, which selectively target and image hypoxic cells
Implementation Method 3
conjugated with fluorescent or radioactive moieties
Implementation Method 4
mapping click contains one of substituted or unsubstituted —N3—, CN, SCN, substituted alkynes for click chemistry
Data Source
AI summary
Described herein are markers, conjugates, compositions and methods for hypoxia imaging, mapping, and therapy. A compound comprising bio-reductively activated (BA) arm, linker arm and a mapping click wherein BA contains one for more of substituted or unsubstituted 2/4/5-substituted nitroimidazoles, or substituted benzotriazene-1,4-dioxides, or substituted 1,2,3/1,2,4-triazoles, or substituted 1,4-benzoquinones, or a combination of two homo-or hetero BA moieties, wherein linker arm contains C1-16 alkane, alkene, alkyne, alicyclic or aromatic linkers with or without hetero atoms as in ethers, amine, esters, acid, amides, 5 and 6 membered sugar sings with the substitution as described above, both monosaccharides and disaccharides, wherein mapping click contains one of substituted or unsubstituted —N3-, CN, SCN, substituted alkynes for click chemistry. Said compound undergoes in situ click reaction after its distribution in cells or tissues to link to a reporting group which may be unchelated or chelated with a metal-radioactive or non-radioactive-, or a radiohalogen for PET/SPECT, or a dye for fluorescent/optical reporting group, thus accomplishing hypoxia imaging.