Novel nanoparticles deliver innovative cancer chemoimmunotherapy

University of Pittsburgh researchers, US, have designed a new immunotherapy approach that silences a gene involved in immunosuppression. When combined with an existing chemotherapy drug and packaged into tiny nanoparticles, the therapy shrunk tumours in mouse models of colon and pancreatic cancer.

This immunotherapy process, published in Nature Nanotechnology,  involved a lipid called phosphatidylserine (PS), which is usually found inside the tumour cell membrane’s inner layer 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 chemotherapy drugs fluorouracil and oxoplatin (FuOXP) led to increased levels of Xkr8, a protein that controls 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 eliminate cancer cells that lingered after chemotherapy.

The team designed snippets of genetic code called short interference RNA (siRNA), which shuts down production of Xkr8. After packaging siRNA and FuOXP together into dual-action nanoparticles, the next step was targeting them to tumours.

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

The surface of the nanoparticles were decorated with chondroitin sulphate and PEG. These compounds help the nanoparticles target tumours and avoid healthy tissue by binding to cell receptors, and prolonging the length of time they remain in the bloodstream.

When injected into mice, about 10 percent of the nanoparticles made their way to their tumour- a significant improvement over most other nanocarrier platforms. The dual-action nanoparticles dramatically reduced the migration of immunosuppressing PS to the cell surface compared to nanoparticles containing the chemodrug FuOXP alone.

The mice treated with nanoparticles containing both FuOXP and siRNA had better tumour 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 tumour size compared to animals that received those carrying just one therapy.

The study also showed 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 tumour growth and survival in mice.

“There are two innovative aspects of our study: the discovery of a new therapeutic target and a new nanocarrier that is very effective in selective delivery of immunotherapy and chemotherapeutic drugs,” said Dr Song Li, professor of pharmaceutical sciences in the Pitt School of Pharmacy and UPMC Hillman Cancer Centre investigator.

“I’m excited about this research because it’s highly translational. We don’t know yet whether our approach works in patients, but our findings suggest that there is a lot of potential.”