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Advanced type of nanoparticles could help fight hard-to-treat cancers
Nanoparticles, or tiny molecules that can deliver a payload of drugs and other agents, hold promise for treating cancer. Scientists can build them in various forms from different materials, often as porous, crystal-like structures made of a lattice of metal and organic compounds, or as capsules that enclose their contents in a shell. When these particles are injected into a tumor, they can deliver treatments that attack cancer cells directly or complement other treatments such as immunotherapy and radiation. In a joint effort between cancer specialists and chemists, researchers at the University of Chicago have formulated an advanced type of nanoparticle...
Advanced type of nanoparticles could help fight hard-to-treat cancers
Nanoparticles, or tiny molecules that can deliver a payload of drugs and other agents, hold promise for treating cancer. Scientists can build them in various forms from different materials, often as porous, crystal-like structures made of a lattice of metal and organic compounds, or as capsules that enclose their contents in a shell. When these particles are injected into a tumor, they can deliver treatments that attack cancer cells directly or complement other treatments such as immunotherapy and radiation.
In a joint effort between cancer specialists and chemists, University of Chicago researchers have formulated an advanced type of nanoparticle that carries a bacterial-derived compound that targets a powerful immune system signaling pathway called STING. The particles disrupt the tumor's blood vessel structure and stimulate an immune response. This approach also helps overcome resistance to immunotherapy treatments in certain pancreatic tumors and also improves response to radiation therapy in gliomas.
This was an unusual collaboration between medicine and inorganic chemistry to address this unmet need to treat tumors that cannot be treated with conventional therapy. We were able to provide an immunostimulant that itself has antitumor activity and enabled radiation and immunotherapy to cure these tumors.”
Ralph Weichselbaum, MD, Daniel K. Ludwig Distinguished Service Professor and Chair of Radiation and Cellular Oncology at UChicago
The study, “Zinc cyclo di-AMP nanoparticles target and suppress tumors via endothelial STING activation and tumor-associated macrophage reinvigoration,” was published on October 26, 2022 in Nature Nanotechnology.
Cold, hot and hotter tumors
As is always the case with cancer, some tumors prove resistant to even the most modern treatments. Immunotherapy unleashes the body's immune system to find and destroy cancer cells, but the tumors must be "hot" or inflamed for these treatments to be effective. So-called “cold” tumors, which are not inflamed, can hide from the immune system but continue to grow and form metastases.
In two studies published in 2014, Weichselbaum and other UChicago researchers showed that mice lacking a protein pathway called STING did not develop an effective immune response to cancer when combined with immunotherapy or high-dose radiation treatment. STING, short for Stimulator of Interferon Genes Complex, is a crucial part of the process the immune system relies on to detect threats – such as infections or cancer cells – characterized by the presence of DNA that is damaged or in the wrong place, inside the cell but outside the nucleus.
Since then, STING has become a tempting target for treatments to heat cold tumors and make already hot tumors hotter. However, this was challenging because drugs that stimulate the STING pathway are typically very small and water-soluble. When injected intravenously, they are rapidly excreted by renal filtration and in high doses can cause toxicity to normal tissues.
Wenbin Lin, PhD, James Franck Professor of Chemistry at UChicago, specializes in building nanostructures that can deliver a variety of compounds to tumors. Nanoparticles tend to get trapped in tumors because of their tangled vascular and lymphatic systems, allowing them to deliver more of their payloads exactly where they are needed. Lin has developed a new type of particle called nanoscale coordination polymers (NCPs) that have a nontoxic zinc phosphate core surrounded by lipid layers. These NCPs have the advantage that they can be engineered for controlled release, further increasing drug deposition in tumors.
Lin, who is trained as an inorganic chemist, says his experience in developing particles with different properties puts him in a unique situation when working on medical treatments. "It is a unique technology that is well suited to the delivery of many drugs. We already know how to modify the surface so that they can circulate in the blood and not be engulfed by macrophages," he said.
A versatile technology
In the new study, Weichselbaum and Lin's teams loaded the NCPs with a nucleotide called cyclic dimeric adenosine monophosphate (CDA). CDA is a piece of DNA that bacteria produce when they invade a host; its sudden appearance—whether through an infection or through a nanoparticle—triggers the STING pathway and the host's innate immune response to fight the cancer.
This enhanced immune response attacked the tumors in a variety of ways, suppressing tumor growth and preventing metastasis in several types of cancer. It destroyed endothelial cells in the blood vessels of tumors and further increased the deposition of CDA in tumors. Surprisingly, it also improved the ability of tumor-associated macrophages that had infiltrated tumors to present antigens that mark them for attack by anti-tumor T cells.
Additionally, this approach made non-inflamed, cold pancreatic tumors more susceptible to immunotherapy treatment. It was also effective against glioma by effectively crossing the blood-brain barrier to reverse resistance to immunotherapy and enhance the effects of radiation treatments.
"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," Weichselbaum said.
Lin, who founded a start-up company called Coordination Pharmaceuticals to develop NCPs, is excited about their potential for further clinical applications.
"This has huge potential because we are 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 looking for ways to optimize formulations to get more NCP candidates into clinical trials. Small startups can advance clinical candidates in much less time than large pharmaceutical companies."
Source:
Reference:
Yang, K., et al. (2022) Zinc-cyclic di-AMP nanoparticles target and suppress tumors through endothelial STING activation and tumor-associated macrophage resuscitation. Nature nanotechnology. doi.org/10.1038/s41565-022-01225-x.
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