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Updated: Jun 7, 2026

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An Enzyme-Responsive Gd(III) MRI Probe for Visualizing β-Hexosaminidase A Activity.

Minrui Luo1, Jian-Hong Tang1,2, Yiqing Lei1

  • 1Departments of Chemistry, Molecular Biosciences, Neurobiology, and Radiology, Northwestern University, Evanston, Ilinois 60208, United States.

ACS Sensors
|June 5, 2026
PubMed
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Researchers developed a new magnetic resonance imaging contrast agent that specifically detects the activity of a lysosomal enzyme often linked to cancer and metabolic diseases. This probe remains inactive until it encounters the target enzyme, at which point it changes its structure to improve image clarity. Laboratory tests confirmed that the agent is safe for cells and effectively highlights enzyme activity, offering a potential tool for non-invasive medical diagnostics.

Area of Science:

  • Molecular imaging research within HexA-Gd diagnostic development
  • Analytical chemistry and biomedical engineering

Background:

Current diagnostic techniques often struggle to visualize specific enzyme activity within living tissues with high spatial resolution. No prior work had resolved the limitations of existing contrast agents regarding enzyme-specific activation. Prior research has shown that magnetic resonance imaging provides excellent anatomical detail but frequently lacks molecular sensitivity. That uncertainty drove the development of smart probes capable of responding to biochemical triggers. Scientists have long sought methods to monitor lysosomal function without invasive procedures. This gap motivated the creation of agents that alter their physical properties upon enzymatic cleavage. Previous studies established that gadolinium-based complexes can serve as effective signal enhancers. However, achieving high selectivity for specific enzymes like beta-hexosaminidase A remains a significant challenge in the field.

Purpose Of The Study:

The study aims to design and evaluate a bioresponsive magnetic resonance imaging contrast agent for detecting beta-hexosaminidase A activity. Researchers sought to address the need for selective molecular imaging tools in complex biological environments. The team focused on creating a probe that remains inactive until triggered by a specific enzymatic reaction. This design strategy intends to reduce background noise during diagnostic imaging procedures. The authors investigated whether a self-immolative linker could effectively modulate gadolinium coordination. They aimed to demonstrate that this structural change leads to a measurable increase in relaxivity. The motivation for this work stems from the requirement for non-invasive methods to monitor lysosomal function. By developing this agent, the researchers hope to provide a new platform for visualizing disease-related enzyme activity.

Keywords:
contrast agentsenzyme-responsive probehexosaminidasemagnetic resonance imagingmolecular imagingself-immolativemolecular imaginggadolinium probeenzyme activitylysosomal disorderscontrast enhancement

Frequently Asked Questions

The researchers propose that the probe utilizes a self-immolative linker, which undergoes structural rearrangement upon enzymatic cleavage. This process alters the coordination environment of the gadolinium ion, thereby increasing the longitudinal relaxivity from 3.06 to 3.78 mM-1 s-1 in phosphate-buffered saline.

The team employed a nonresponsive control agent, NDO3A-Gd, to validate the specificity of the signal changes. This comparison confirmed that the observed relaxivity shifts were unique to the target-responsive design rather than general environmental factors.

The authors indicate that high-field phantom imaging at 7 Tesla was necessary to confirm the relaxivity enhancement in a controlled environment. This technical step provided validation for the longitudinal and transverse relaxivity values of 5.06 and 7.67 mM-1 s-1, respectively.

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Main Methods:

The investigation utilized a synthetic chemistry approach to construct the bioresponsive probe architecture. Researchers performed relaxometric assessments in phosphate-buffered saline to determine signal changes at 1.4 Tesla. They employed time-course experiments to track the speed of activation following enzyme addition. The team conducted phantom imaging at 7 Tesla to validate performance under high-field conditions. Proton nuclear magnetic resonance dispersion profiling provided insights into the underlying molecular behavior of the complex. Scientists used colorectal cancer cell lines to evaluate the biological compatibility and uptake efficiency of the compound. They assessed cytotoxicity levels to ensure the safety of the agent for potential medical use. Finally, the group compared the performance of the new probe against a nonresponsive control to confirm selective activation.

Main Results:

The strongest finding indicates that the probe exhibits a longitudinal relaxivity of 3.06 mM-1 s-1 in its pristine form. Upon enzymatic conversion, this value increases to 3.78 mM-1 s-1, demonstrating successful signal modulation. Time-course measurements confirmed significant signal shortening within 20 minutes of exposure to the enzyme. High-field imaging at 7 Tesla yielded a longitudinal relaxivity of 5.06 mM-1 s-1. The transverse relaxivity was measured at 7.67 mM-1 s-1 during these high-field phantom tests. Proton nuclear magnetic resonance dispersion profiling highlighted that the mechanism relies on hydration number modulation. Cell-based experiments showed that the agent is internalized efficiently by colorectal cancer cells. The results also confirmed that the probe maintains low cytotoxicity throughout the evaluation period.

Conclusions:

The authors propose that this probe serves as a viable platform for tracking specific enzymatic processes in biological systems. Their data suggest that the self-immolative mechanism successfully modulates signal intensity upon target exposure. The researchers conclude that the observed relaxivity enhancement supports the utility of this agent for non-invasive diagnostic applications. They indicate that the low cytotoxicity profile makes the compound suitable for future cellular investigations. The study demonstrates that the probe maintains structural integrity until it encounters the intended enzyme. The findings imply that this approach could be adapted for monitoring various lysosomal storage disorders. The team suggests that the rapid activation kinetics provide a distinct advantage for real-time imaging requirements. Finally, the authors maintain that their design strategy offers a robust framework for creating future bioresponsive imaging agents.

The researchers utilized proton nuclear magnetic resonance dispersion profiling to elucidate the molecular basis of the signal change. This data type allowed them to confirm that the modulation of the hydration number, or q-value, drives the observed increase in contrast.

The study measured the longitudinal relaxivity, denoted as r1, under specific conditions of pH 7.4 and 37 degrees Celsius. This measurement confirmed that the agent remains stable in its pristine state before activation by the target enzyme.

The authors suggest that this platform holds potential for noninvasive imaging of cancer and lysosomal storage disorders. They propose that the efficient cellular internalization observed in SW480 cells supports its future application in disease-relevant contexts.