Trigger-Activatable Sugar Conjugates for Selective Cancer Labeling
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Solution Overview
Problem
Current cancer-targeting strategies face challenges in selectively accumulating drugs in cancer cells while minimizing exposure to healthy tissues, as most strategies rely on cancer cell surface proteins, which have low density and are not cancer-specific, and existing approaches like monoclonal antibodies are costly and immunogenic.
Innovation Solution
Development of compounds comprising an azidosugar moiety, a trigger-responsive moiety, and a self-immolative linker that can be selectively expressed on cancer cell surfaces, allowing for controlled metabolic labeling and targeted drug delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If cancer cell surface proteins are used as targets, then binding specificity is improved, but target density and cancer-specificity deteriorate
Solution Approach 1:
The patent changes the target parameter from proteins to sugars, specifically utilizing sugar moieties that are enriched on cancer cell surfaces. This parameter change enables targeting based on sugar density and cancer-specific sugar expression patterns, resolving the contradiction between protein binding specificity and target density.
Solution Approach 2:
The patent employs sugar analogs and metabolically engineered sugar conjugates that mimic natural sugar structures but with modified properties. These copying strategies allow selective accumulation in cancer cells through metabolic pathways while providing enhanced targeting capability compared to natural sugars.
2Measurement precision
If monoclonal antibodies are used as targeting ligands, then cancer-specificity is improved, but production cost and immunogenicity worsen
Solution Approach 1:
The patent replaces expensive monoclonal antibodies with smaller, more economical sugar-based targeting agents. These sugar conjugates and metabolically engineered compounds serve as disposable-like molecules that can be easily administered and metabolized, eliminating the need for costly antibody production while maintaining cancer-specificity.
Solution Approach 2:
The patent extracts the targeting function from complex protein-based antibodies and isolates it into simplified sugar-based molecules. By taking out the essential targeting capability and expressing it through sugar metabolism and binding, the patent achieves cancer-specificity at lower cost and reduced immunogenicity.
3Quantity of substance
If unnatural sugars are used for metabolic labeling, then cell surface labeling is improved, but selectivity for cancer cells deteriorates
Solution Approach 1:
The patent applies local quality by modifying sugar structures to exploit local differences in cancer cell metabolism. Specific sugar moieties are designed to be preferentially metabolized or accumulated in cancer cells due to their unique metabolic pathways, achieving both labeling and selectivity simultaneously.
Solution Approach 2:
The patent employs preliminary action through trigger-responsive moieties that are activated only after internalization by cancer cells. These moieties remain dormant during circulation but are activated intracellularly through cancer-specific triggers, ensuring selective labeling occurs only in cancer cells that have taken up the conjugate.
4Measurement precision
If trigger-responsive moieties are incorporated, then cancer selectivity is improved, but device complexity worsens
Solution Approach 1:
The patent segments the molecular structure into distinct functional modules: sugar moiety for binding, trigger-responsive moiety for activation, and self-immolative linker for release. This segmentation allows each component to perform its specific function independently, managing complexity through modular design while achieving high cancer selectivity.
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
Enables selective metabolic labeling and therapeutic targeting of cancer cells, potentially overcoming the limitations of existing cancer-targeting strategies by utilizing azidosugars and trigger-responsive linkers for controlled drug release.
Implementation Method 1
a trigger-responsive moiety that is cleaved by a trigger, and a self-immolative linker, wherein the self-immolative linker is covalently bonded to the nonulopyranosonic acid moiety or the galactopyranosyl moiety, and to the trigger-responsive moiety
Implementation Method 2
it was recently discovered that unnatural sugars (e.g., tetraacetyl N-azidoacetylmannosamine (Ac4ManAz)) can be metabolically expressed on the cell surface
Data Source
AI summary
Disclosed are compounds for the selective labeling of cell-surface sugars in cancer cells. The compounds are activatable by triggers specific to cancer cells, and, when metabolized, label a cancer cell surface sugar with an azide chemical group. Facilitated by a click chemistry reaction, combination of the cell surface-expressed azide with a alkynyl-drug conjugate enables efficient targeted drug delivery to cancer cells with reduced toxicity. Also disclosed are compounds for delivering a drug to an azide-bearing cancer cell, and methods of treating cancer using the compounds.