Researchers at the University of Chicago Medicine Comprehensive Cancer Center have developed a nanomedicine that enhances the penetration and accumulation of chemotherapy drugs in tumor tissues, effectively killing cancer cells in mice.
The study, published in Science Advances, addresses a limitation of chemotherapy. Although chemotherapy is the primary treatment option for most cancers, much of the drug is quickly broken down by enzymes or cleared by the kidneys before reaching tumor tissue. Additionally, a significant amount of the drug affects healthy tissues, causing toxic side effects.
To overcome this challenge, one emerging approach has been to package chemotherapy drugs into nanoparticles. These particles can carry chemotherapy agents directly to tumors. While promising, nanomedicine still requires significant improvement in its ability to deposit drugs into tumor cells.
Wenbin Lin, the James Franck Professor of Chemistry at the University of Chicago, is a pioneer in developing nanoparticles for medical imaging and drug delivery. The new study from his lab reports a novel approach to enhance nanomedicine’s effects, which proved effective in mice and which they hope to move to pre-clinical testing.
Chemotherapy drugs reach tumor cells by crossing over from blood vessels into neighboring tumor tissue. However, cancer cells often recruit nearby blood vessels to invade other tissues; these hastily created vessels are often abnormal—creating irregular blood flow patterns and making it difficult for a drug to penetrate tumor tissue effectively.
Scientists examined a pathway known as STING (stimulator of interferon genes). STING activation disrupts tumor vasculature—the arrangement of blood vessels—and increases the leakiness of blood vessels near tumors. Previous attempts to activate STING had failed to achieve desired outcomes.
Lin and his team designed a tiny polymer that encapsulates both STING and the chemotherapy drug. This leverages STING activators' unique property by delivering them along with chemotherapy drugs, with the idea that STING activation increases blood vessel permeability around tumors and thus enhances chemotherapy’s effects.
“We have discovered a novel way to use STING activators to disrupt tumor vasculature to basically enhance drug delivery to tumors without enhancing them to other tissues,” said Lin.
“STING activators haven't worked very well by themselves, but by creating nanomedicine, I think this could also make STING activators work alone or in combination, which I think is an important contribution,” said Ralph Weichselbaum, the Daniel K. Ludwig Distinguished Service Professor and Chair of Radiation and Cellular Oncology at UChicago and senior author on the new study.
The research team evaluated therapy's antitumor effects on multiple kinds of tumors in mice and found strong antitumor effects with large tumor growth inhibition and high cure rates.
“We noted that radiation activates STING like a pathogen because of double-stranded breaks introduced by radiation and importantly that STING agonists might be useful in cancer therapy,” said Weichselbaum.
The scientists also noted that STING may have other effects beyond blood vessel permeability. The STING pathway gets activated by invading pathogens like bacteria or viruses as well as abnormal DNA from cancer cells; it drives inflammatory responses to clear unwanted cells. STING activation also increases T cell infiltration and turns immunologically “cold” tumors into so-called “hot” or inflamed tumors, making them more responsive to immunotherapy agents like immune checkpoint inhibitors.
This work emerged from long-standing collaboration between UChicago’s Physical Sciences Division and Biological Sciences Division. “This is one of the highlights of my career—to be able to work with Dr. Lin because I have hugely benefited from his expertise in engineering nanoparticles to solve clinical problems,” said Weichselbaum.
“The next steps are more validation studies and preparing for scaling technology for potential human testing,” said Lin.
Additional UChicago authors included Xiaomin Jiang, Taokun Luo, Kaiting Yang, Morten Lee, Jing Liu, Langston Tillman, and Wenyao Zhen.
Citation: “STING activation disrupts tumor vasculature to overcome the EPR limitation and increase drug deposition,” Jiang et al., Science Advances, July 17, 2024.
Funding: National Institutes of Health.
—Adapted from an article by UChicago Comprehensive Cancer Center published by Biological Sciences Division.