A new weapon in the fight against disease

Illustration of cancer cell biology

The study presents two innovative aspects: the discovery of a new therapeutic target and the development of an effective nanocarrier for the selective delivery of immunotherapeutic and chemotherapeutic drugs.

Researchers have developed anticancer nanoparticles that can deliver innovative chemoimmunotherapy.

According to a new study published in the journal Nature NanotechnologyUniversity of Pittsburgh researchers have developed anticancer nanoparticles that simultaneously deliver chemotherapy and a new immunotherapy.

The new immunotherapy, which silences a gene involved in immunosuppression, has been shown to shrink tumors in mouse models of colon and pancreatic cancer when combined with chemotherapy and packaged in nanoparticles.

“There are two innovative aspects of our study: the discovery of a novel therapeutic target and a novel nanocarrier that is highly effective in the selective delivery of immunotherapy and chemotherapy drugs,” said senior author Song Li, MD, Ph.D. ., professor of pharmaceutical sciences at the Pitt School of Pharmacy and UPMC Hillman Cancer Center investigator. “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 is a lot of potential.”

FuOXP siRNA nanoparticles

Electron microscope image of nanoparticles containing the chemotherapy drug FuOXP and a novel siRNA immunotherapy that blocks Xkr8 expression. Credit: Chen et al., 2022, Nature Nanotechnology10.1038/s41565-022-01266-2

Chemotherapy is a mainstay of cancer treatment, but residual cancer cells can persist and cause cancer to come back. This process involves a lipid called phosphatidylserine (PS), which is usually found within 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.

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

led 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 take up cancer cells that persisted after chemotherapy.

Proposed strategy for FuOXP-mediated immunosuppression and Xkr8 siRNA effect

Proposed strategy on how FuOXP chemotherapy can lead to immunosuppression (left side of image) in tumors, but a new immunotherapy that blocks the expression of a protein called Xkr8 can reactivate the immune system (right side of image). The new study found that FuOXP led to increased levels of Xkr8, a protein that redistributes PS to the cell surface, resulting in immunosuppression due to more T-regulatory cells and tumor-promoting M2 macrophages. However, when the researchers blocked Xkr8 expression with siRNA, PS remained within the inner layer of the cell membrane, enhancing the immune system by increasing the number of tumor-fighting T cells, M1 macrophages and dendritic cells. Credit: Chen et al., 2022, Nature Nanotechnology10.1038/s41565-022-01266-2

In an independent study recently published in

Li and his team designed snippets of genetic code called short interference RNA (siRNA), which shuts down the production of specific proteins — in this case, Xkr8. After packaging siRNA and FuOXP together into dual-action nanoparticles, the next step was targeting them to tumors.

Song Li

Song Li, M.D., Ph.D., professor of pharmaceutical sciences in the Pitt School of Pharmacy and UPMC Hillman Cancer Center investigator. Credit: Jan Shaw

Nanoparticles are typically too large to cross intact blood vessels in healthy tissue, but they can reach cancer cells because tumors sometimes have poorly developed vessels with holes that allow them passage. But this tumor-targeting approach is limited because many human tumors do not have large enough holes for 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 cross intact blood vessels without relying on holes,” said Li.

To develop such a ferry, 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 on both tumor blood vessels and tumor cells and prolonging the length of time they remain in the bloodstream.

FuOXP siRNA Nanoparticles and Mouse Colon Cancer Cells

Fluorescence microscopy image showing FuOXP-siRNA nanoparticles (red) effectively taken up by mouse colon cancer cells. Cell nuclei appear as blue circles. Credit: Chen et al., 2022, Nature Nanotechnology, 10.1038/s41565-022-01266-2

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

The dual-action nanoparticles dramatically reduced the migration of immunosuppressing PS to the cell surface compared to nanoparticles containing the chemodrug 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 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 just one therapy.

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

The 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 their sights set on translating their novel therapy to the clinic, the team is now looking to validate their findings with additional experiments and further evaluate potential side effects.

References: “Targeting Xkr8 via nanoparticle-mediated in situ co-delivery of siRNA and chemotherapy drugs for cancer immunochemotherapy” by Yuang Chen, Yixian Huang, Qinzhe Li, Zhangyi Luo, Ziqian Zhang, Haozhe Huang, Jingjing Sun, LinXinTian Zhang, Runzi Sun, Daniel J. Bain, James F. Conway, Binfeng Lu and Song Li, 24 November 2022, Nature Nanotechnology.
DOI: 10.1038/s41565-022-01266-2

“Mobilizing phospholipids on tumor plasma membrane implicates phosphatidylserine externalization blockade for cancer immunotherapy” by Weihong Wang, Shaoxian Wu, Zhanpeng Cen, Yixin Zhang, Yuang Chen, Yixian Huang, Anthony R. Cillo, Joshua S. Prokopec, Giovanni Quarato, Dario A.A. Vignali, Jacob Stewart-Ornstein, Song Li, Binfeng Lu and Yi-Nan Gong, 1 November 2022, Cell Reports.
DOI: 10.1016/j.celrep.2022.111582

The study was funded by the National Institutes of Health. 

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