Smart molecular probe aims to make hidden breast cancer cells glow during surgery

Surgical removal of a tumor remains the primary defense against most solid cancers, yet distinguishing the outer edge of a tumor from healthy tissue is one of the operating room’s most persistent challenges. In aggressive, structurally erratic cancers, this boundary can be especially difficult to find, and leaving behind even a microscopic cluster of residual cancer cells significantly elevates the risk of the disease returning and spreading. At the University of Texas at San Antonio, Syed Muhammad Usama, PhD, assistant professor of chemical biology in the Department of Chemistry, is developing a novel molecular “smart probe” designed to make hidden cancer cells glow in real time during surgery, giving surgeons cleaner margins and patients a lower risk of recurrence. The clinical potential of the work has earned funding from the Max and Minnie Tomerlin Voelcker Fund, including a recent award of $450,000 that will help accelerate the project from basic organic chemistry into translational models.

Usama’s research focuses on triple-negative breast cancer, an exceptionally aggressive subtype that constitutes roughly 15% to 20% of all breast cancer cases. The phrase “triple-negative” refers to the absence of the three receptors typically found on breast cancer cells: estrogen, progesterone and human epidermal growth factor receptor 2, or HER2. Because these receptors are the targets that many breast cancer therapies and hormone treatments latch onto, triple-negative breast cancer is resistant to many first-line treatments. “Surgical resection is the primary intervention for more than half of all cancer patients every year,” Usama said. “But when you are dealing with a subtype as aggressive as triple-negative breast cancer, relying solely on a surgeon’s sight and touch to clear the tumor margins is a major clinical challenge.”

Fluorescence-guided surgery is an emerging approach in which patients are injected with fluorophores, targeted fluorescent dyes, prior to an operation. During surgery, specialized near-infrared lasers illuminate these dyes, giving the medical team a glowing blueprint of the tumor and its borders. Unfortunately, today’s fluorescent dyes also need to bind to the three receptors that triple-negative breast cancer lacks, leaving surgeons without a reliable optical map for this subtype. Rather than searching for markers on the outside of the cell, Usama’s laboratory is targeting proteins inside the cells that help fuel tumor growth from within. These proteins are known as cyclin-dependent kinases 4 and 6, or CDK4/6. While normal cells keep these proteins relatively controlled, most triple-negative breast cancer tumors produce much more of them.

To reach these cells, the researchers are pairing an FDA-approved drug called palbociclib, which naturally binds to CDK4/6, with a deep-tissue-penetrating near-infrared fluorogenic dye called cyclizing heptamethine cyanine, or c-Cy7, which Usama developed. Working in tandem, the two compounds form a “smart probe” called c-Cy7-pal. What sets this probe apart is its activation mechanism. Conventional imaging dyes are “always on,” glowing continuously from the moment they are injected, which creates background noise because the dye pools in healthy tissues and makes it hard for surgeons to see the edges of the tumor. Usama’s engineered probe instead acts like an intelligent warning light, illuminating cancerous tissue and going dark elsewhere.

“Our c-Cy7-pal probe only activates and illuminates after binding to the specific intracellular proteins overexpressed in the tumor,” Usama explained. “This gives us dramatically higher target-to-background contrast, making a clear distinction between tumor and healthy tissue.” The switch-flipping is triggered by changes in the target area’s internal chemistry, specifically how water-repelling or electrically charged the surrounding environment is. While traveling through healthy tissue, the probe naturally twists into a closed, dark state. When the probe penetrates a cancer cell and locks onto the targeted CDK4/6 protein, the shift in polarity coaxes the molecule to snap open into a charged state, switching on its fluorescence. Because the probe is still in development, its performance in patients has not yet been demonstrated; the Voelcker Fund award is intended to move the technology into translational models that could test whether the approach can reshape the surgical oncology landscape.

The project is also part of UT San Antonio’s broader mission to cultivate an agile STEM workforce in South Texas. With support from the Voelcker Fund Young Investigator Award, Usama has recruited and trained five PhD students and 12 undergraduate students in chemistry, biochemistry, biology and biomedical engineering. He has redesigned junior-level biochemistry coursework and launched a specialized graduate-level chemical biology course to expand student access to hands-on laboratory training in molecular design, drug development and bioimaging. “Our students aren’t just reading about these concepts — they are actively synthesizing the probes, running the biological assays and learning how to communicate complex science,” Usama said. “To see their growth has been tremendous; they are the medical and scientific leaders of the future.”

Subject of Research: Fluorescence-guided surgery and molecular probe development for triple-negative breast cancer

Article Title: Chemist develops probe to illuminate breast cancer cells at UT San Antonio

Article References: Chemist develops probe to illuminate breast cancer cells at UT San Antonio. Original publication (Bibliographic details unavailable.)

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Keywords: fluorescence-guided surgery, triple-negative breast cancer, CDK4/6, molecular probe, palbociclib, chemical biology, surgical oncology, UT San Antonio, Chemist, develops, probe, illuminate