November 29, 2022 -- University of Pittsburgh (Pitt) researchers have designed cancer-fighting nanoparticles that co-deliver an existing chemotherapy drug along with a novel immunotherapy that silences an immunosuppression gene.
Their research, published November 24 in the journal Nature Nanotechnology, found that the therapy shrunk tumors in mice with colon and pancreatic cancer.
Residual cancer cells often cause relapse after chemotherapy. The lipid phosphatidylserine (PS), usually found inside the tumor cell membrane, migrates to the cell surface in response to chemotherapy drugs. There, PS protects remaining cancer cells from the immune system.
The researchers found that treatment with chemotherapy drugs fluorouracil and oxoplatin (FuOXP) led to increased levels of Xkr8, a protein that controls PS distribution. Hence, blocking Xkr8 could prevent cancer cells from shunting PS to the cell surface, allowing immune cells to destroy them.
The team designed genetic code snippets called short interference RNA (siRNA), which shut down Xkr8 production. After packaging siRNA and FuOXP into dual-action nanoparticles, the researchers filled the nanoparticle surfaces with chondroitin sulfate and polyethylene glycol (PEG). These compounds help the nanoparticles target tumors by binding to tumor cell receptors, 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 nanocarriers. The dual-action nanoparticles reduced the migration of immunosuppressing PS to cell surfaces compared to nanoparticles containing FuOXP alone.
In mice with colon and pancreatic cancer, mice treated with nanoparticles containing both FuOXP and siRNA had more cancer-fighting T cells, fewer immunosuppressive regulatory T cells, and decreased tumor sizes compared with those that received placebo or FuOXP alone.
The researchers also found that FuOXP nanoparticles with or without siRNA increased expression of programmed cell death 1 (PD-1), which acts like immune system brakes. But adding a PD-1 inhibitor drug to "release" the brakes resulted in significantly improved survival in mice. Clinical trials are an eventual goal.
"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," senior author Dr. Song Li, PhD, professor of pharmaceutical sciences in the Pitt School of Pharmacy, said in a statement.