When drugs are administered, understanding their precise distribution and binding within the body has long been a challenge for scientists. Traditional approaches can determine drug concentrations in organs but cannot identify which specific cells the drugs interact with or detect unexpected sites of action.
"Usually we have almost no idea, after a drug enters the body, how it actually interacts with its target," said Professor Li Ye, N. Paul Whittier Endowed Chair at Scripps Research and Howard Hughes Medical Institute investigator. "It's been a black box until now."
A team led by Ye has introduced an imaging technique called vCATCH that reveals individual cells where drugs bind throughout an entire mouse body. Their study, published in Cell, applied this method to two commonly used cancer medications. The findings showed that one of these drugs binds unexpectedly in heart tissue and blood vessels, which may help explain its cardiovascular side effects.
Clinical trials can demonstrate whether a drug is effective and identify common adverse reactions, but they do not show what the drug does at the cellular level across all tissues. Previous tracking methods either analyzed ground-up tissue samples or relied on low-resolution imaging techniques such as radioactive labeling. These provided only general information about organ-level distribution rather than cell-specific details.
In 2022, Ye’s laboratory developed CATCH to illuminate drug binding sites on organ surfaces like those of the brain. The new research extends this approach to map binding throughout entire organs—including deep tissues in the brain, heart, and lungs.
The CATCH method works for covalent drugs—medications that form permanent bonds with their targets—by adding a small chemical handle before injection into mice. After binding occurs in vivo, researchers treat collected tissues with a fluorescent tag and copper molecule to trigger a rapid chemical reaction (click chemistry), making it possible to visualize exactly where each drug molecule has attached.
Click chemistry was pioneered at Scripps Research by K. Barry Sharpless, who received the 2022 Nobel Prize in Chemistry for this work.
To adapt vCATCH for use across different organ systems, Ye’s group addressed technical challenges related to copper absorption by tissue proteins—which previously limited visualization to organ surfaces—by pre-treating tissues with excess copper and performing multiple cycles of staining without increasing background noise due to click chemistry’s selectivity.
"Click chemistry is intrinsically highly specific and efficient," Ye explained. "That allows us to fully saturate the system without causing off-target effects."
Given that whole-body imaging generates massive amounts of data per animal studied, engineers worked alongside researchers to develop artificial intelligence-based analysis tools capable of automatically identifying drug-bound cells throughout organs such as the brain.
Ye’s team tested vCATCH using two targeted cancer therapies: ibrutinib (Imbruvica) for blood cancers and afatinib (Gilotrif) for non-small cell lung cancer. The mapping confirmed afatinib’s widespread presence in lung tissue as expected while revealing that ibrutinib also binds immune cells in liver, heart tissue, and blood vessels—a pattern consistent with some known side effects including irregular heartbeat and bleeding problems.
"Now researchers can look more precisely at those cells and understand why ibrutinib is binding to them," said Ye.
The technology’s potential applications extend beyond oncology drugs; current efforts include investigating whether cancer treatments preferentially bind tumor versus healthy cells and determining which brain cell types are affected by psychiatric medications such as antidepressants or antipsychotics.
"This could be an incredibly valuable tool for testing late-stage drug candidates to make sure they are strongly binding their targets and don't have any unwanted binding in other organs," Ye said.
