Bioreducible N-oxide Probes for Deep-Tissue Hypoxia Imaging
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Solution Overview
Problem
Current methods for detecting hypoxia, such as oxygen-sensitive electrodes and optical imaging with fluorescent probes, are invasive or suffer from poor resolution and high background noise, limiting the ability to confidently discern specific hypoxic regions in deep tissues.
Innovation Solution
Development of hypoxia-responsive probes (HyPs) that undergo bioreduction in the absence of oxygen, featuring a N-oxide-based trigger, allowing for photoacoustic imaging with enhanced signal detection in the near-infrared region, enabling non-invasive and specific hypoxia detection in deep tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If oxygen-sensitive electrodes are used for hypoxia detection, then measurement precision is improved, but device complexity and invasiveness increase
Solution Approach 1:
The patent replaces the mechanical/electrical oxygen-sensitive electrode system with an optical imaging system using fluorescent probes. The probe contains an oxygen-sensitive moiety that undergoes chemical reaction with oxygen, converting a mechanical measurement system into a chemical-optical system that can be imaged non-invasively
Solution Approach 2:
The patent introduces a fluorescent probe as an intermediary substance that mediates between the target oxygen molecules and the detection system. The probe contains an oxygen-sensitive moiety that reacts with oxygen, and a fluorescent reporter that provides the optical signal, acting as a bridge between the chemical target and the imaging modality
2Ease of operation
If fluorescent probes are used for optical imaging, then ease of operation is improved, but measurement precision deteriorates due to light scattering and limited penetration
Solution Approach 1:
The patent changes the optical parameters by using near-infrared (NIR) fluorescent probes that operate in the second optical window (650-950 nm). This wavelength range experiences minimal absorption and scattering by biological tissues, allowing deep tissue penetration while maintaining spatial resolution. The probe design incorporates NIR-absorbing chromophores to achieve this
3Difficulty of detecting and measuring
If PET-based hypoxia detection is used, then detection capability is improved, but measurement precision deteriorates due to high background and limited spatial resolution
Solution Approach 1:
The patent applies local quality by designing probes with tissue-specific targeting moieties that confer selective affinity for hypoxic tumor regions. The probe accumulates preferentially in hypoxic areas through passive EPR effect and active targeting, creating localized high concentration at the disease site while maintaining low background in normal tissues, thereby improving signal-to-noise ratio and spatial resolution
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
HyPs provide a non-invasive, high-resolution method for detecting hypoxia with minimal background noise, enabling reliable detection of oxygen deficiencies in both acute and chronic conditions, suitable for various disease models including tumors and peripheral artery disease.
Implementation Method 1
HyPs features an N-oxide-based trigger that can undergo facile bioreduction in the absence of oxygen
Implementation Method 2
Photoacoustic (PA) imaging is a rapidly emerging modality that utilizes near-infrared (NIR) light from a pulsed laser source to induce temperature and pressure fluctuations in tissue, producing ultrasound waves that can be detected using acoustic transducers
Implementation Method 3
wherein the compound absorbs electromagnetic radiation at about the near infrared (NIR) region of the electromagnetic spectrum
Data Source
AI summary
Hypoxia occurs when limited oxygen supply impairs physiological functions and is a pathological hallmark of many diseases including cancer and ischemia. Thus, detection of hypoxia can guide treatment planning and serve as a predictor of patient prognosis. Current methods suffer from invasiveness, poor resolution and low specificity. To address these limitations, various hypoxia-responsive probes (HyPs) for photoacoustic imaging are disclosed. The emerging modality converts safe, non-ionizing light to ultrasound waves, enabling acquisition of high-resolution 3D images in deep tissue. The HyPs feature an N-oxide trigger that is reduced in the absence of oxygen by haem proteins such as CYP450 enzymes. Reduction of HyPs produce a spectrally distinct product, facilitating identification via photoacoustic imaging. HyPs exhibit selectivity for hypoxic activation in vitro, in living cells and in multiple disease models in vivo. HyPs are also compatible with NIR fluorescence imaging, establishing its versatility as a multimodal imaging agent.