PITTSBURGH, Nov. 24, 2022 — Researchers at the University of Pittsburgh have engineered cancer-fighting nanoparticles that co-deliver a chemotherapy drug and a new immunotherapy, according to a new Nature’s nanotechnology study published today.
The new immunotherapy approach silences a gene that researchers have found to be involved in immunosuppression. When combined with an existing chemotherapy drug and packaged in tiny nanoparticles, the therapy shrank tumors in mouse models of colon and pancreatic cancer.
“Our study has two innovative aspects: the discovery of a new therapeutic target and a new highly effective nanocarrier in the selective delivery of immunotherapies and chemotherapeutic drugs,” said lead author Song Li, MD, Ph. .D., professor of pharmaceutical sciences at the Pitt School of Pharmacy and researcher at UPMC’s Hillman Cancer Center. “I am excited about this research because it is highly translational. We don’t yet know if our approach works in patients, but our results suggest there’s a lot of potential.
Chemotherapy is a mainstay of cancer treatment, but residual cancer cells can persist and cause tumor relapse. This process involves a lipid called phosphatidylserine (PS), which is usually found inside the inner layer of the tumor cell membrane but migrates to the cell surface in response to chemotherapy drugs. On the surface, PS acts as an immunosuppressant, protecting remaining cancer cells from the immune system.
The Pitt researchers found that treatment with the chemotherapy drugs fluorouracil and oxoplatin (FuOXP)
leads to increased levels of Xkr8, a protein that controls the distribution of PS on the cell membrane. This finding suggested that blocking Xkr8 would prevent cancer cells from shunting PS to the cell surface, allowing immune cells to mop up cancer cells that persisted after chemotherapy.
In an independent study recently published in Cell reportsYi-Nan Gong, Ph.D., an assistant professor of immunology at Pitt, has also identified Xkr8 as a new therapeutic target to stimulate the anti-tumor immune response.
Li and his team engineered snippets of genetic code called short interfering RNAs (siRNAs), which shut down the production of specific proteins – in this case, Xkr8. After packaging siRNA and FuOXP together into dual-action nanoparticles, the next step was to target them to tumors.
The nanoparticles are generally too large to pass through intact 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. But this tumor targeting approach is limited because many human tumors don’t have holes large enough for the nanoparticles to pass through.
“Like a ferry carrying people from one side of the river to the other, we wanted to develop a mechanism that allows nanoparticles to pass through intact blood vessels without relying on holes,” Li said.
To develop such a tray, the researchers decorated the surface of the nanoparticles with chondroitin sulfate and PEG. These compounds help the nanoparticles target tumors and avoid healthy tissue by binding to cell receptors common to tumor blood vessels and tumor cells and extending the time they stay in the bloodstream.
When injected into mice, approximately 10% of the nanoparticles travel to their tumor, a significant improvement over most other nanocarrier platforms. Previous analysis of published research found that, on average, only 0.7% of nanoparticle doses hit their target.
Dual-acting nanoparticles significantly reduced the migration of immunosuppressive PS to the cell surface compared to nanoparticles containing the chemo-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 anticancer T cells and fewer immunosuppressive regulatory T cells than animals given placebo or FuOXP doses.
As a result, mice that received the siRNA-FuOXP nanoparticles showed a dramatic decrease in tumor size compared to animals that received those carrying only one treatment.
According to Li, the study also pointed to the potential of combining FuOXP-siRNA nanoparticles with another type of immunotherapy called checkpoint inhibitors. Immune checkpoints such as PD-1 act as brakes on the immune system, but checkpoint inhibitors work to release the brakes and help immune cells fight cancer.
Researchers found that FuOXP nanoparticles with or without siRNA increased PD-1 expression. But when they added a PD-1 inhibitor drug, the combination therapy had drastic improvements in tumor growth and survival in mice.
With the goal of translating their new therapy into the clinic, the team is now looking to validate their findings with additional experiments and further evaluate potential side effects.
Other researchers who contributed to this study were 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., all of Pitt or UPMC.
This work was supported by the National Institutes of Health (R01CA219399, R01CA223788, and R01CA219716).
About University of Pittsburgh School of Pharmacy
The University of Pittsburgh School of Pharmacy has been nurturing leaders who have directed the future of pharmacy for more than 135 years. We investigate, discover and create ways to improve patient health and, through partnerships, change practice and improve the effectiveness of care. Pitt Pharmacy ranks in top 10 NIH-funded research and top 15 US News and World Report among pharmacy schools. The School of Pharmacy leads the way in education, personalizing education and enabling students to improve faster. Chartered in 1878, the School of Pharmacy is one of the oldest schools of pharmacy in the nation.
About UPMC Hillman Cancer Center
UPMC Hillman Cancer Center connects patients to the integrated expertise of clinicians, academic researchers, specialty programs, and leading treatment centers. By partnering with the University of Pittsburgh School of Medicine, UPMC’s Hillman Cancer Center, the only National Cancer Institute-designated comprehensive cancer center in the region, is accelerating breakthroughs from the lab to clinical practice around the world. UPMC – nationally ranked by US News and World Report for Excellence in Cancer Care – has more than 70 cancer treatment centers in Pennsylvania, Ohio, New York and Maryland, as well as centers in Ireland and Italy. Backed by the collective strength of UPMC, UPMC Hillman Cancer Center provides cutting-edge treatments and the latest clinical research to transform cancer research, care and prevention, one patient at a time.
The title of the article
Targeting of Xkr8 via nanoparticle-mediated in situ co-delivery of siRNA and chemotherapy drugs for cancer immunochemotherapy
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