Nanoparticle-based targeted delivery unleashes the full power of anti-cancer drugs

A new paper in Cell Reports Medicine details the development of a nanoparticle-based system that delivers concentrated chemotherapy specifically to cancer cells and not normal cells, potentially allowing clinicians to administer higher, more effective doses of anti-cancer drugs while avoiding some of the well-known toxic side effects.

Glucose metabolism in cancer cells and healthy cells

Cancer cells are extremely difficult to distinguish from healthy cells — this is how they avoid detection by our bodies’ immune systems. It therefore remains a physiological challenge to kill cancer cells without damaging healthy cells in the process. To avoid toxic side effects, clinicians must administer treatments like chemotherapy and immunotherapy agents in limited doses, thereby restricting their effectiveness.

To address this problem, researchers at the University of Chicago Medicine Comprehensive Cancer Center sought to develop a drug delivery method that was released specifically near tumor cells. They achieved this by exploiting a well-known phenomenon called the "Warburg effect," which involves a difference in the way cancer cells metabolize glucose compared to healthy cells. Instead of fully breaking down glucose to carbon dioxide and water to generate a lot of energy, cancer cells typically break down glucose only part way to a molecule called lactate, generating a smaller amount of energy.

“Depending on the cancer cell type, some solid tumors can accumulate more than 40-fold higher lactate concentration than normal,” said senior author Xiaoyang Wu, PhD, Associate Professor in the Ben May Department of Cancer Research at the University of Chicago. “So, the idea was to take advantage of this dramatic change in a specific metabolite and create a drug delivery system that specifically targets these lactate-rich environments.”

How does nanoparticle drug delivery work?

Wu and his colleagues used nanoparticles — specifically, microscopic silica particles with pores into which a variety of cancer drugs can be loaded. These particles, small enough to be injected into the bloodstream, have been used to improve drug delivery for decades, but only a few are currently approved for clinical use in cancer treatment.

The novelty of Wu’s nanoparticle is that it’s controlled by a lactate-specific switch. The switch has two parts: first is lactate oxidase, an enzyme that binds and breaks down lactate and produces hydrogen peroxide, and second is a hydrogen peroxide-sensitive molecule that caps the nanoparticle, preventing the drug from being released.

This way, when the nanoparticle is in lactate-poor environments, like healthy tissues in the body, the capping material remains intact, preventing the drug from causing any damage to these tissues. But in a lactate-rich environment like the area within and around a tumor, the lactate oxidase begins breaking down lactate, generating a high enough concentration of hydrogen peroxide to trigger the degradation of the capping material and release of the drug.

“I had been thinking about how to specifically target lactate for a long time, since it is so enriched in tumors,” said Wu. “But lactate itself is not a very reactive chemical, so it was difficult to create a system that chemically responded to lactate. The biggest innovation was designing a switch that translated this cancer-specific signal to a chemically active molecule: hydrogen peroxide.”

Using mice to model two different forms of cancer, Wu and his colleagues tested the nanoparticle’s ability to specifically release its cargo in tumors. As they expected, the drug was specifically released in the lactate-rich tumor environment, and not in healthy tissues. Compared to directly injecting the drug itself into the bloodstream — the typical method of administering chemo drugs — the nanoparticle was able to deliver a 10-fold higher concentration of the drug in the tumor. They also found that this delivery method enhanced outcomes like slowing tumor growth and increased survival relative to direct drug injection.

Another advantage of this method is that lactate concentration is already measured in cancer patients, since it’s a useful biomarker to indicate cancer progression.

“It's very easy to quantify lactate in human patients using non-invasive imaging methods like MRI,” Wu said. “And since we can accurately quantify lactate in tumors, it would be a very good means of screening patients for clinical trials and predicting how they would respond to the treatment.”

Broad potential applications for lactate-gated nanoparticles

In initial tests of their nanoparticle platform, Wu and his colleagues focused largely on a common drug called doxorubicin, which is a primary therapy for various cancers like breast cancer, sarcoma, lymphoma and acute lymphocytic leukemia. However, they also showed that several other chemotherapy drugs and immunotherapy drugs can be successfully loaded onto the nanoparticles.

“By designing this specific switch that controls drug release based on a well-characterized change in the cancer microenvironment, we hope to improve the safety profile for many drugs and allow an increased dose to be administered in order to more effectively kill cancer cells,” he said.

Cancer is not the only disease associated with increased lactate concentration. Patients with arthritis, for example, may have higher levels of lactate in their joints due to chronic inflammation. Because anti-inflammatory medications also suppress the immune response for the whole body, they can also put the patient at higher risk for infections. The lactate-gated nanoparticle, with its specific targeting of lactate-rich environments, would help avoid this general adverse effect just as it does with toxic cancer drugs.

Toward clinical implementation and future research

Wu co-founded an oncology startup called Alnair Therapeutics through the Polsky Center for Entrepreneurship and Innovation to take this research to the next level.

“In the lab, you only need a tiny batch. For clinical trials, though, we need a 10-fold greater amount, because humans are so big! So, scaling up the manufacturing process is our current challenge,” Wu said. “The first goal is to make manufacturing work with Doxil [brand name for doxorubicin], since it’s so well-characterized. But we’re very interested in expanding the platform to other cancer therapy drugs, because high toxicity is a common problem.”

Wu is also interested in further researching the unique aspects of tumor metabolism.

“There are many more unknown differences between cancer cell metabolism and regular cell metabolism,” he said. “My personal interest is to figure out more about what's changing in tumor cells and what kind of chemical signals we can use to target cancers, maybe not only through drug delivery, but through other approaches as well.”

The study, “Enabling tumor-specific drug delivery by targeting the Warburg effect of cancer,” was published in Cell Reports Medicine in January 2025. Additional authors include Jian Zhang, Tony Pan, Jimmy Lee, Sarah Ann King, Erting Tang, Yifei Hu, Lifeng Chen, Alex Hoover, and Jun Huang at the University of Chicago, Sanja Goldberg at Safra Children’s Hospital, Tel Aviv, Linyong Zhu at East China University of Science & Technology, Shanghai, Oliver S. King at the University of California, Irvine, Orange, CA, and Benjamin Dekel at Tel Aviv University, Tel Aviv.

This study was supported by National Institutes of Health grants R01OD023700, R21AR080761, R01DA047785, and R01AR78555, the Cancer Research Institute (CRI) Technology Impact Award, the Samuel Waxman Cancer Research Foundation, the Alan B. Slifka Foundation and Israel Cancer Fund for Pediatric Sarcoma Grant, the Rally Foundation Outside the Box Grant, the University of Chicago Comprehensive Cancer Center Duckworth Family Commercial Promise Award, the Cancer Immunotherapy Team Science Award, the Pancreatic Cancer SPORE grant, the UCHAP pilot award, and the Ullman Family Team Science Award (to X.W.) and National Institutes of Health New Innovator Award (to J.H.).