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Scientists can now see exactly which cells medicines bind to throughout the body, revealing hidden targets that may explain side effects before drugs reach patients.
Using this approach in mice, researchers traced two cancer drugs across organs and tissues, exposing binding patterns that standard tests miss.
Where drugs bind in the body
Unexpected drug binding can cause side effects when a molecule latches onto the wrong protein in healthy tissues.
The work was led by Professor Li Ye at Scripps Research, where he studies how medicines engage targets across tissues.
His lab tracks covalent drugs, medicines that bond permanently to proteins, to explain why treatments help some cells but harm others.
Organ averages hide risks
Standard pharmacokinetics, measuring how drugs move through the body, often reports organ averages that hide rare cell targets.
Researchers may grind tissue for chemistry tests or use low-resolution scans that blur signals across thousands of cells.
That blur can miss a drug binding in heart muscle or blood vessels, where small numbers of cells matter.
Better drug mapping
In 2022, Ye’s group introduced CATCH, a method that highlighted drug binding mainly on organ surfaces.
That earlier approach worked on thin tissue sections, so fluorescent tags had trouble reaching deep regions of the brain or heart.
The team’s new method, known as vCATCH, builds on CATCH by improving chemical access so that the signal appears in both outer layers and deeper cells.
Researchers modify a covalent drug with a tiny chemical handle, a small add-on for later labeling, before dosing animals.
Once the drug attaches to its target, the animal is sampled, and the chemical handle is linked to a fluorescent dye.
Because the dye is added after dosing, the drug can behave normally while its final binding sites become visible.
Click chemistry labels drugs
The labeling step relies on click chemistry, a reaction that joins two molecules quickly and cleanly, using copper as a helper.
“Click chemistry is intrinsically highly specific and efficient,” explained Professor Ye.
In 2022, the Nobel Prize committee recognized click chemistry as a major advance in chemistry.
Copper blocked deep labeling
A stubborn copper problem in tissue had to be solved before the team described the vCATCH method.
Proteins inside organs can grab copper ions, so less copper reaches deep cells where tagging should happen.
Without enough copper, fluorescent labeling stalls at the surface, leaving the center dark and the map incomplete.
Repeating steps to reach deep cells
The researchers pre-soaked organs with extra copper, then ran up to eight reaction cycles to push the tag deeper.
The first soak fills common copper-binding sites, and fresh reaction mixes keep active copper available as the dye attaches.
High specificity prevents the repeated baths from coating unrelated proteins, so labeled cells remain easier to trust.
Making organs transparent
Dense tissue scatters light, so researchers use tissue clearing – the removal of fats so organs become transparent – before whole-body imaging.
The samples are stabilized with a gel and scanned using a microscope that sweeps a thin sheet of light.
Making the tissue transparent allows the fluorescent tags to be seen in 3D, rather than just on sliced sections.
Handling massive imaging data
Whole-body imaging can generate multiple terabytes of data per mouse, so manual review becomes impossible for any team.
Engineers built computer vision, software that detects objects in images, to flag drug-bound cells across organs automatically.
Those cell counts can later be aligned with anatomical maps to reveal binding patterns that would otherwise go unnoticed.
Mapping two real cancer drugs
The team tested afatinib, sold as Gilotrif, for metastatic non-small cell lung cancer.
The experts also tested ibrutinib, sold as Imbruvica, which carries warnings about bleeding and heart rhythm problems in its U.S. label.
Both drugs form covalent bonds, making them suitable for the tagging approach, but their binding maps can still differ sharply.
Drug binding in lung tissue
In the lungs, afatinib lit up many cell types, consistent with a therapy that blocks a growth-signaling receptor on cells.
The maps showed especially strong binding throughout lung tissue, which helps explain why the drug can reach scattered tumor cells.
This pattern matters because it gives a baseline for judging when other drugs spread too widely or too narrowly.
Linking drug binding to side effects
Heart tissue and blood vessels showed notable ibrutinib binding, a pattern that was not expected from its main cancer target.
The signal appeared in immune cells within the liver and vessel walls, suggesting the drug engages proteins beyond its intended site.
Pinpointing those cells can guide follow-up tests that connect binding to side effects, dose limits, or safer designs.
Limitations and next steps
Interpreting a binding map requires caution, because some signals may reflect off-target effects, drug actions on unintended proteins.
The vCATCH method labels covalent drug probes, so scientists must confirm that each probe keeps the parent drug’s behavior.
Researchers now want to test tumor-bearing mice and brain drugs, including antidepressants and antipsychotics, to see which cell types bind.
By linking drug binding to specific cells, the vCATCH method can turn vague side effects into testable biology in animals.
Even with carefully designed probes and follow-up studies, whole-body maps could guide researchers in selecting drug candidates that target the right cells.
The study is published in the journal Cell.
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