New cancer-fighting nanoparticles co-deliver a chemotherapy and immunotherapy drug

University of Pittsburgh researchers have engineered cancer-fighting nanoparticles that co-deliver a chemotherapy drug and a new immunotherapy, according to a new study. Nature Nanotechnology study published today.

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

There are two innovative aspects of our study: the discovery of a new therapeutic target and a new nanocarrier that is very effective in the selective delivery of immunotherapy and chemotherapy. I’m excited about this research because it’s highly translational. We don’t yet know if our approach works in patients, but our findings suggest there’s a lot of potential.”

Song Li, MD, Ph.D., Senior Author, Professor of Pharmaceutical Sciences at the Pitt School of Pharmacy, and Investigator at the UPMC Hillman Cancer Center

Chemotherapy is a mainstay of cancer treatment, but residual cancer cells can persist and cause the tumor to come back. 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 the remaining cancer cells from the immune system.

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

led to increased levels of Xkr8, a protein that controls the distribution of PS in the cell membrane. This finding suggested that blocking Xkr8 would prevent cancer cells from diverting 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-Nan Gong, Ph.D., assistant professor of immunology at Pitt, also identified Xkr8 as a new therapeutic target for enhancing the antitumor immune response.

Li and his team designed stretches of genetic code called short interfering RNA (siRNA), which stop the production of specific proteins -; in this case, Xkr8. After packaging the siRNA and FuOXP together into dual-acting nanoparticles, the next step was to target them to tumors.

Nanoparticles are usually 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 through. But this tumor-targeted approach is limited because many human tumors don’t have holes large enough for nanoparticles to pass through.

“Like a ferry carrying people from one side of a river to the other, we wanted to develop a mechanism that would allow nanoparticles to pass through intact blood vessels without relying on holes,” Li said.

To develop such a raft, the researchers decorated the surface of the nanoparticles with chondroitin sulfate and PEG. These compounds help nanoparticles target tumors and avoid healthy tissue by binding to common cell receptors on tumor blood vessels and tumor cells and prolonging the time they remain in the bloodstream.

When injected into mice, about 10% of the nanoparticles reached the 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-acting nanoparticles dramatically reduced the migration of immunosuppressant 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 pancreas cancer. Animals treated with nanoparticles containing FuOXP and siRNA had better tumor microenvironments with more cancer-fighting T cells and fewer immunosuppressive regulatory T cells than animals receiving placebo or doses of FuOXP.

As a result, the mice that received the siRNA-FuOXP nanoparticles showed a dramatic decrease in tumor size compared to the animals that received those with just one therapy.

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 like PD-1 act as brakes on the immune system, but checkpoint inhibitors work to 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 inhibitor drug, the combination therapy saw dramatic improvements in tumor growth and survival in mice.

With the aim 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 from Pitt or UPMC.

Source:

Newspaper reference:

Chen, Y. and others (2022) Targeting Xkr8 via in situ co-delivery mediated by siRNA nanoparticles and chemotherapy drugs for cancer immunochemotherapy. Nature Nanotechnology. doi.org/10.1038/s41565-022-01266-2.

New cancer-fighting nanoparticles co-deliver a chemotherapy and immunotherapy drug

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