Novel nanoparticles innovate cancer chemotherapy, immunotherapy

Editor’s pick: According to a new study published today in Nature Nanotechnology, researchers at the University of Pittsburgh have engineered a cancer-fighting Nanoparticles that can simultaneously deliver a chemotherapy drug and a new immunotherapy.

Electron microscope image of nanoparticles containing the chemotherapeutic drug FuOXP and a novel immunotherapeutic siRNA that blocks Xkr8 expression.

Pittsburgh researchers have designed cancer-fighting nanoparticles that can simultaneously deliver chemotherapy drugs and a new type of immunotherapy, according to a new study.

New immunotherapy approach silences a gene researchers have identified as being involved in immune suppression. When combined with existing chemotherapy drugs and packaged into tiny nanoparticles, the therapy shrank tumors in mouse models of colon and pancreatic cancer.

“Our research has two innovative aspects: the discovery of a new therapeutic target and a new nanocarrier that are highly effective in selective delivery,” said senior author Song Li, professor of pharmacy at Pitt School of Pharmacy and investigator at UPMC Hillman Cancer Center. “I’m excited about this study because it’s highly translational. whether the approach is effective for patients, but our findings suggest that there is great potential.”

Chemotherapy is the mainstay of cancer treatment, but residual cancer cells persist and lead to tumor recurrence. The process involves a lipid called phosphatidylserine (PS), which is normally found in the inner layer of tumor cell membranes 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 found that treatment with the chemotherapy drugs fluorouracil and opalin platinum (FuOXP) led to increased levels of Xkr8, a protein that controls the distribution of PS across cell membranes. This finding suggests that blocking Xkr8 prevents cancer cells from shunting PS to the cell surface, allowing immune cells to clear residual cancer cells after chemotherapy.

In an independent study recently published in Cell Reports, Dr. Yi-Nan Gong, Assistant Professor of Immunology at Pitt University, also identified Xkr8 as a new Therapeutic targets to promote anti-tumor immune responses.

The team engineered a stretch of genetic code known as a short interfering RNA (siRNA) that halts the production of a specific protein — in this case, Xkr8 . After packaging siRNA and FuOXP into dual-acting nanoparticles, the next step is 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 blood vessels with tiny holes that allow them pass. But this approach to tumor targeting is limited because many human tumors do not have pores large enough for the nanoparticles to pass through.

“Just like a ferry carries people from one side of a river to the other, we wanted to develop a mechanism for nanoparticles to travel through intact blood vessels independent of pores.” Professor Li said.

To develop such a ferry, the researchers decorated the surface of the nanoparticles with chondroitin sulfate and polyethylene glycol. These compounds help the nanoparticles target tumors and avoid healthy tissue by binding to tumor blood vessels and cellular receptors commonly found on tumor cells, prolonging their residence time in the bloodstream.

When injected into mice, approximately 10 percent of the nanoparticles reached tumors in mice, a significant improvement over most other nanocarrier platforms. A previous analysis of published studies found that, on average, only 0.7 percent of the nanoparticle doses hit the target.

Dual-acting nanoparticles significantly reduced the migration of immunosuppressive PS to the cell surface compared to nanoparticles containing the chemical drug FuOXP alone.

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

As a result, tumor size was significantly reduced in mice receiving siRNA-FuOXP nanoparticles compared to mice receiving only one treatment.

Professor Li said the study also points to the potential 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 work by releasing the brakes to 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 showed significant improvements in tumor growth and survival in mice.

Their goal is to translate their new therapy into the clinic, and the team is now running more experiments to validate their findings and further evaluate potential side effects.

Source: Nature Nanotechnology

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