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Novel nanoparticles deliver innovative cancer

Image: Electron microscope image of nanoparticles containing the chemotherapy drug FuOXP and a novel siRNA immunotherapy that inhibits the expression of Xkr8.
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Credit: Chen et al., 2022, Nature Nanotechnology, 10.1038/s41565-022-01266-2

Pittsburgh, November 24, 2022 Researchers at the University of Pittsburgh have designed cancer-fighting nanoparticles that are involved in delivering a new chemotherapy drug and immunotherapy, according to a new study. Nature’s Nanotechnology Study published today.

A new immunotherapy approach silences a gene that researchers have discovered is involved in immunosuppression. When combined with an existing chemotherapy drug and packaged into tiny nanoparticles, the treatment shrank tumors in mouse models of colon and pancreatic cancer.

said senior author Song Li, MD, PhD, professor of pharmaceutical sciences at the Pitt School of Pharmacy and UPMC-Hellman Cancer Center investigator. “I’m excited about this research because it’s so translational. We don’t know yet if our approach works for patients, but our findings suggest there’s a lot of potential.”

Chemotherapy is a mainstay of cancer treatment, but the remaining cancer cells can persist and cause tumor relapse. This process involves a fatty substance called phosphatidylserine (PS), which is normally found within the inner layer of the cancer cell membrane but migrates to the cell surface in response to chemotherapy drugs. Ostensibly, PS acts as an immunosuppressant, protecting remaining cancer cells from the immune system.

Pitt researchers found that treatment with the chemotherapy drugs fluorouracil and oxoplatin (FuOXP)

It led to increased levels of Xkr8, a protein that controls the distribution of PS to the cell membrane. This result indicates that blocking Xkr8 will prevent cancer cells from transducing PS to the cell surface, allowing immune cells to clear out cancer cells that remained after chemotherapy.

In an independent study recently published in Cell ReportsYi Nangong, Ph.D., assistant professor of immunology at Pitt, also identified Xkr8 as a novel therapeutic target for enhancing the anti-tumor immune response.

Lee and his team engineered snippets of genetic code called short interfering RNA (siRNA), which stop the production of certain proteins — in this case, Xkr8. After putting siRNA and FuOXP together into dual-acting nanoparticles, the next step was to target them to tumors.

Nanoparticles are usually too big to pass through healthy blood vessels in healthy tissue, but they can reach cancer cells because tumors sometimes have poorly developed vessels with holes that allow them to pass through. But this tumor-targeting approach is limited because many human tumors do not have holes large enough for nanoparticles to pass through.

“Like a ferry that takes people from one side of a river to the other,” Lee told me, “we wanted to develop a mechanism that would allow nanoparticles to cross healthy blood vessels without relying on holes.”

To develop such a statement, the researchers decorated the surface of the nanoparticles with chondroitin sulfate and PEG. These compounds help the nanoparticles target tumors and spare healthy tissue by binding to cell receptors common to both cancer blood vessels and tumor cells and prolonging their survival in the bloodstream.

When injected into mice, about 10% of the nanoparticles found their way into the tumor – a significant improvement over most other nanocarrier platforms. An analysis of previous published research found that, on average, only 0.7% of nanoparticle doses reach their target.

The dual-action nanoparticles significantly reduced migration of immunosuppressive PS to the cell surface compared to nanoparticles containing the chemotherapy drug FuOXP alone.

Next, the researchers tested their platform in mouse models of colon and pancreatic cancer. Animals treated with nanoparticles containing both FuOXP and siRNA had better tumor microenvironments with more cancer-fighting T cells and fewer immunosuppressive regulatory T cells than animals that received placebo or doses of FuOXP.

As a result, mice that received siRNA-FuOXP nanoparticles showed a significant reduction in tumor volume compared to animals that received only one treatment.

According to Li, the study also indicated the possibility of combining FuOXP-siRNA nanoparticles with another type of immunotherapy called checkpoint inhibitors. Immune checkpoints like PD-1 act like brakes on the immune system, but checkpoint inhibitors release the brakes and help immune cells fight cancer.

The researchers found that FuOXP nanoparticles with or without siRNA increased PD-1 expression. But when they added a PD-1-inhibiting drug, the combination therapy led to dramatic improvements in tumor growth and survival in the mice.

With their eyes set on translating their new treatment into the clinic, the team is now looking to validate their findings with additional trials and evaluate potential side effects further.

Other researchers who contributed to this study are Yuang Chen, MS, Yixian Huang, Ph.D. Qinzhe Li, MS, Zhangyi Luo, BS, Ziqian Zhang, MS, Haozhe Huang, MS, Jingjing Sun, Ph.D. LinXinTian Zhang, BS, Runzi Sun, Ph.D. , Daniel J. Bain, Ph.D. James F. Conway, Ph.D. and Binfeng Lu, Ph.D. , every Pitt or UPMC.

This work was supported by the National Institutes of Health (R01CA219399, R01CA223788 and R01CA219716).

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About the University of Pittsburgh School of Pharmacy
The University of Pittsburgh School of Pharmacy has been developing leaders who drive the future of pharmacy for more than 135 years. We research, discover and create ways to improve patients’ health and, through partnerships, change practices and improve the efficiency of care. Pet Pharmacy ranks in the top 10 in research funded by the National Institutes of Health and in the top 15 in research funded by the National Institutes of Health US news and world report among pharmacy schools. The College of Pharmacy is leading the way in education, personalizing education and making students experts faster. Founded in 1878, the School of Pharmacy is among the oldest schools of pharmacy in the country.

About UPMC Hillman Cancer Center
UPMC-Hellmann Cancer Center connects patients with the integrated expertise of leading physicians, academic researchers, specialized programs, and treatment centers. By partnering with the University of Pittsburgh School of Medicine, UPMC-Hellmann Cancer Center, the only National Cancer Institute-designated comprehensive cancer center in the region, is accelerating breakthroughs from the laboratory to clinical practice around the world. UPMC – Ranked Nationally By US News & World Report For excellence in cancer care – it has more than 70 cancer treatment sites throughout Pennsylvania, Ohio, New York and Maryland as well as centers in Ireland and Italy. Powered by the collective strength of UPMC, the UPMC-Hellmann Cancer Center provides groundbreaking treatments and the latest clinical investigations to transform cancer research, care, and prevention–one patient at a time.

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