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A polymeric package deal: Diagnosing and treating breast cancer with a single nanoparticle complex

The drug pipeline—the process through which a potential new drug gets discovered, tested, approved, and marketed—is a notoriously long and arduous process, and even the most promising drugs can languish or die on the road to the clinic.

Many drugs, particularly those used in cancer and other complex diseases, can present with high toxicity or can dissolve poorly, limiting the body's ability to carry it to its destined location and curtailing the drugs' safety and therapeutic effectiveness. A critical strategy to limiting a drug's toxic side effects is for it to reach only its pathogenic target and nothing else.

A group of researchers from the lab of Larry Marnett, the Mary Geddes Stahlman Professor of Cancer Research, paired a precisely targeted imaging agent to an anticancer agent and found that they could specifically attack cancer cells and not normal cells with it.

Their work was performed in collaboration with School of Engineering faculty members Craig Duvall and Rebecca Cook, and was in Molecular Pharmaceutics.

The imaging agent was created by Jashim Uddin, research associate professor of biochemistry and Marnett lab member, and was designed to target the enzyme cyclooxygenase-2.

COX-2 carries out a key step in the production of a chemical released during inflammation, is greatly upregulated in inflamed tissues, plays a critical role in tumorigenesis, and is known to colocalize with reactive oxygen species in pathologic cells and tissues. The imaging agent was designed to help clinicians detect colorectal adenomas, which are currently under-detected by the standard diagnostic tool: colonoscopies.

"Today, the call for personalized medicine demands a new nanoplatform for the simultaneous delivery of both imaging and therapeutic agents to preneoplastic or neoplastic tissues for imaging to be performed not only before or after, but also during a treatment procedure," Uddin said. Such combinations of therapeutic and diagnostic agents are called theranostics.

In their recent advance, Uddin and the Marnett lab hypothesized that, if they could combine a COX-2-targeted optical imaging agent with a cytotoxic COX-2 inhibitor, they might be able to both visualize and attack a tumor at the same time.

Uddin synthesized and packaged the imaging agent fluorocoxib Q with the COX-2 inhibitor chemocoxib A into polymeric nanoparticle capsules that were designed to disassemble upon reaching their target; in this study, the target was breast cancer cells, which were enriched with reactive oxygen species and COX-2. Once released, the CA could attack the cells and the FQ could visualize the cancer cells both in cells and live animals.

"This strategy allowed us to overcome a limitation in the field: choosing between achieving higher specificity or enabling real-time monitoring."

In their paper, Uddin and colleagues described three primary findings:

1. Selective cytotoxicity toward cancer cells: FQ-CA-NPs reduced the viability of breast cancer cells but spared primary human mammary epithelial cells, indicating that the FQ-CA-NPs had cancer-selective therapeutic effects.
2. Reactive oxygen species–activated tumor targeting and fluorescence: In mice, intravenous FQ-CA-NPs released their cargo when activated by the ROS present in the tumor microenvironment, enabling the fluorescence-guided visualization of the drug's delivery.
3. Enhanced drug retention in tumors and therapeutic efficacy: Bioanalytical assays and cell staining confirmed that tumors retained the drug at higher rates than normal cells and that tumor growth was inhibited thanks to COX-2, validating the therapeutic effects of FQ-CA-NPs.

Moving forward, Uddin and the Marnett lab are focusing on advancing targeted cancer therapies using their drug–imaging agent conjugate—or variations of it.

"We're particularly interested in validating that tumor-specific delivery by targeting tumors' ROS-rich environment in a variety of cancers," Uddin said. "We're also interested in expanding safety studies for our NP complexes and exploring potential synergy between them and other chemotherapeutic drugs, such as checkpoint inhibitors."

This research is paving the way toward the development of a modular nanomedicine platform that could redefine precision oncology by merging targeted delivery, real-time monitoring, and multimodal therapy.

"This work is laying the groundwork for IND-enabling studies, which we hope to complete within the next two to three years," Uddin said. Investigational new drug studies are the first step toward clinical studies involving patients. "We're very excited at the prospect of bringing this theranostic tool into the clinic."