STING (stimulator of interferon genes) are adaptor proteins that help the immune system detect infections and cancer cells. Drugs that stimulate STINGs (STING agonists) can enhance the ability of the immune system to detect cancer cells. This clinical utility of STING agonists has however been restricted by the poor ability of these small, water-soluble molecules to reach tumors in adequate concentrations since they are rapidly cleared away by the kidneys. Besides, STING agonists can be toxic to normal cells.
A study published in the journal Nature Nanotechnology on Thursday, reports the design and development of a nanoparticle polymer called ZnCDA with robust tumor-targeting capacity, that encapsulates a nucleotide messenger molecule found in bacteria called cyclic dimeric adenosine monophosphate (CDA) that is a potent STING agonist. The study is a collaborative effort by cancer specialists and chemists from the University of Chicago (UChicago), University Medical Center Hamburg-Eppendorf (UKE) in Germany, University of North Carolina at Chapel Hill, and Peking and Tsinghua Universities in China,
Using a diverse set of preclinical cancer models, the researchers show, when ZnCDA is injected intravenously, CDA remains in the systemic blood circulation for an extended period and efficiently targets tumors, at a single dose. ZnCDA acts by disrupting endothelial cells that line the blood vessels that supply blood to the tumors, causing the nanoparticles to accumulate in the tumors.
ZnCDA targets immune cells called tumor-associated macrophages (TAMs) to influence key immune mechanisms of antigen processing and presentation that in turn modulates T-cell responses against the tumor cells. Moreover, ZnCDA synergistically enhances the efficacy of radiotherapy and immune checkpoint blockade immunotherapy, boosting response to radiation therapy in glioma and overcoming resistance to immunotherapy in certain pancreatic cancers.
“This was an unusual collaboration between medicine and inorganic chemistry to solve this unmet need of treating tumors that are intractable to conventional therapy,” said Ralph Weichselbaum, MD, the Daniel K. Ludwig Distinguished Service Professor and Chair of Radiation and Cellular Oncology at UChicago. “We were able to deliver an immune stimulant that has anti-tumor activity on its own, and enabled radiation and immunotherapy to cure these tumors.” Earlier studies by Weichselbaum’s team and others had showed, mice that lack the STINGs did not mount an effective immune response to cancer upon immunotherapy or high-dose radiation.
Wenbin Lin, PhD, the James Franck Professor of Chemistry at UChicago, specializes in building nanoparticles for cancer drug delivery. Lin has developed nanoscale coordination polymers (NCPs) that have a non-toxic zinc phosphate core surrounded by layers of lipids. These NCPs can be engineered for controlled release, further increasing the amount of drug that reaches and accumulates in tumors.
“It’s a unique technology that is well-suited for delivering many drug agents. We already know how to modify the surface so they can circulate in the blood and not be engulfed by macrophages,” said Lin.
Lin has formed a startup company called Coordination Pharmaceuticals to develop NCPs and is excited about their clinical use. “This has tremendous potential because we’re not limited to a single compound. We can formulate other nucleotides and use other drugs in the same NCP,” he said. “The technology is versatile, and we are exploring ways to optimize formulations to take more NCP candidates into clinical trials. Small startups can advance clinical candidates in a much shorter amount of time than big drug companies.”
In the current study, Weichselbaum and Lin’s teams loaded the NCPs with CDA. CDA triggers the STING pathway and boosts the host’s innate immune response. The invigorated immune response attacks tumors by suppressing tumor growth, preventing metastasis, disrupting tumor blood vessels, increasing the accumulation of drugs in tumors, and enhancing antigen presentation by TAMs, to fight cancer.
“That’s the brilliant part of these nanoformulations. We were able to encapsulate a STING agonist that is extremely potent and promotes both innate and adaptive immunity,” said Weichselbaum.