DDAO Derivatives for Pathogen Detection via pH-Dependent Charge
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Solution Overview
Problem
Current near-infrared (NIR) fluorescent labels are bulky and possess stable electric charges, which hinder their ability to effectively target pathogens due to reduced affinity and cellular uptake, making them unsuitable for timely and sensitive detection of microbial infections in body tissues.
Innovation Solution
Development of small-size NIR fluorophores, such as derivatives of DDAO or 7-aminoDDAO, with improved spectral properties that preserve targeting capabilities and are suitable for bioconjugation, enabling effective imaging of fungal pathogens and bacterial infections using Fluorescent Molecular Tomography (FMT).
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If conventional NIR dyes are used to enhance solubility through stable electric charge groups, then solubility is improved, but the size increases and affinity to targets decreases
Solution Approach 1:
The patent changes the charge parameter from stable permanent charge to dynamic pH-dependent charge. The carboxylic acid groups remain uncharged at acidic pH (enhancing membrane permeability and affinity) and become charged at physiological pH (enhancing solubility). This dynamic parameter change resolves the contradiction between solubility and molecular size/affinity.
2Ease of manufacture
If conventional NIR dyes with stable positive charge are used, then solubility is improved, but affinity to targets and cell permeability are reduced
Solution Approach 1:
The patent applies parameter changes by making the charge state pH-dependent rather than stable. The carboxylic acid groups are uncharged at acidic pH (high affinity to targets) and charged at physiological pH (good solubility). This dynamic parameter change resolves the contradiction between solubility and target affinity.
3Illumination intensity
If bulky NIR fluorescent labels are used, then light emission properties are improved, but the ability to penetrate cells and bind to targets is hindered
Solution Approach 1:
The patent uses parameter changes in the charge state of carboxylic acid groups to achieve a dual benefit: small molecular size for cell penetration and target binding, while maintaining sufficient solubility through pH-dependent charging. This resolves the contradiction between light emission properties and molecular size.
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 small-size NIR fluorophores provide enhanced light-emission properties and are useful in various biomedical applications, allowing for the sensitive detection and monitoring of microbial infections in vivo, offering an alternative to radionuclides and improving the accuracy of pathogen identification.
Implementation Method 1
Fluorescence Molecular Tomography (FMT) is a powerful approach to image microbial infections in body tissues. It is based on using fluorescently labeled compounds that recognize pathogen-specific targets, thereby rendering the pathogen cells fluorescent after binding to the targets.
Implementation Method 2
body tissues have a transparency window in the region 650-800 nm with a maximal transparency at 680 nm, which enables non-invasive imaging of NIR dyes in the living body
Data Source
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AI summary
The present invention provides compounds useful as novel near-infrared labels, compositions containing these compounds, and methods of using the near-infrared labels to identify targets in vitro, in situ and in vivo. The invention also provides small or large molecule conjugates between targeting agents and NIR labels, as well as methods and kits thereof, that can be used in diagnostics and treatment of diseases related to microbes in mammalian animals.