Purdue University researchers are developing and validating patent-pending nanoparticles modified with poly(lactic-co-glycolic acid), or PLGA, adenosine triphosphate (ATP) to enhance the effectiveness of immunotherapy against malignant tumors.
Nanoparticles slowly release drugs that induce immunogenic cell death (ICD) in tumors. ICDs produce tumor antigens and other molecules that bring immune cells into the tumor's microenvironment. The researchers attached ATP to the nanoparticles, which also recruit immune cells to the tumor to initiate an anti-tumor immune response.
Professor Yoon Yeo is leading researchers at the College of Pharmacy, the Metabolite Profiling Facility at the Bindley Life Sciences Center, and the Purdue Cancer Institute to develop nanoparticles. Yeo is her associate department chair and the Lillian Barboul Thomas Professor of Industrial and Molecular Pharmacology and Biomedical Engineering. She is also a member of the Purdue Institute for Drug Discovery and the Purdue Institute for Cancer Research.
The researchers validated their study using paclitaxel, a chemotherapy drug used to treat several types of cancer. They found that tumors grew more slowly in mice treated with paclitaxel surrounded by ATP-modified nanoparticles than in mice treated with paclitaxel with unmodified nanoparticles.
“When combined with existing immunotherapy drugs, the ATP-modified and paclitaxel-loaded nanoparticles eliminated tumors in mice and protected them from rechallenge with tumor cells,” Yeo said.
The study was published in a peer-reviewed journal. ACS Nano.
Challenges to delivering systemic immunotherapy
Immunotherapy is a promising approach to fighting cancer, but Dr. Yeo said it does not help many patients because they do not have the strong immune cells needed to fight tumors.
Professor Yeo said, “Pharmacological agents that activate immune cells can be administered directly to the tumor.” “Activated immune cells then circulate in the bloodstream, allowing the immune system to fight not only the treated tumor but also untreated tumors in distant locations.”
However, Yeo said most tumors with poor prognosis cannot always be located or accessed. Therefore, topical treatment may not be effective. She and her team envisioned systemic delivery of immunotherapy, but there were challenges.
Professor Yeo said, “For successful systemic administration, the active ingredient that stimulates anti-tumor immune response must be present in the tumor at the same time to exert a joint effect on the target.” “Additionally, the ingredient must remain active until it reaches the tumor but must not induce toxic off-target effects. Moreover, carriers traditionally used for topical drug delivery may be incompatible with blood components, limiting systemic application. It provides utility.”
Yeo and her colleagues used biocompatible polymer nanoparticles to deliver immunotherapeutic compounds and modified them to safely activate the immune system.
“We used poly(lactic-co-glycolic acid), or PLGA, nanoparticles, based on the polymer’s strong track record in FDA-approved products and its routine use for systemic delivery of poorly soluble drugs,” Yeo said.
Tests confirmed that ATP-modified PLGA nanoparticles were well tolerated in mice upon multiple systemic injections. They were able to recruit dendritic cells, immune cells that recognize tumor antigens and bring in specialized immune cells to fight the tumor.
“Furthermore, nanoparticles have been shown to modulate the release of paclitaxel, minimizing systemic toxicity,” Yeo said.
next development steps
Yeo and her colleagues will continue their research with ATP-modified nanoparticles.
“We are currently studying how to improve how we deliver nanoparticles to tumors and how to combine them with other treatments that could avoid resistance to nanoparticle-delivered immunotherapies,” Yeo said. “To fund these efforts, we will be applying for ongoing support from the National Institutes of Health. We are also open to industry partnerships to bring this technology to the clinic.” Yeo and her research team received funding from the National Institutes of Health, the National Center for Advancing Translational Science, the Indiana Clinical and Translational Science Institute, and the Purdue Cancer Institute.