Researchers have developed a nanoparticle-based approach to overcome the immunosuppressive microenvironment of tumours. The study, published in Nature Nanotechnology, detailed the development of the nanoparticle packaging of gene-silencing RNA molecules combined with existing chemotherapy. The new approach reduced tumour size in mouse models of pancreatic and colon cancer.
Cancers evade the immune system
The immune system plays a crucial role in eliminating cancer cells from the body. However, some cancers can evade the immune response. One way is by increasing the migration of a lipid molecule, known as phosphatidylserine (PS), from the inner membrane to the surface. PS serves as a signal for immune cells to disarm. This means the cancer cells are not eliminated. PS exposure on the surface is regulated by enzymes called scramblases. The study focussed on the scramblase Xkr8.
Researchers at the University of Pittsburgh developed a novel strategy combining existing chemotherapy and an Xkr8 gene-silencing RNA within a new nanoparticle (NP) carrier.
Song Li, senior author and Professor of Pharmaceutical Sciences in the University of Pittsburgh School of Pharmacy said, “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.”
Good things come in small packages
The researchers first showed that chemotherapy increased the expression of Xkr8 in tumours. Fluorouracil and oxoplatin (FuOXP) chemotherapy drugs were packed into NPs and compared to NPs that were empty. Cells treated with the FuOXP-NPs had higher levels of Xkr8 mRNA transcripts than cells treated with the empty NPs.
Since Xkr8 promotes PS export to the cell membrane, the researchers investigated it as a potential therapeutic target. The team designed small non-coding RNA molecules, called short interference RNA (siRNA), that shut down the production of Xkr8 (siXkr8). FuOXP and siXkr8 were packaged into tiny NPs, called PMBOP (figure 1).
The NPs were targeted to the tumour microenvironment (TME) by coating them with chondroitin sulphate (CS) and polyethylene glycol (PEG). These compounds honed the NPs to the TME because they interacted with receptors that were highly expressed on the surrounding tumour vasculature and cells. Compared to the free siRNA and other NP variations, the PEG-CS coated NPs accumulated the most at the tumour sites in mice (figure 2).
The researchers showed that around 10% of the injected NP dose reached the tumour. This is significantly higher than previous NP carriers. Comparted to FuOXP-NP, siXkr8/FuOXP-NP reduced migration of PS to the cell surface. In turn, this improved the immunosuppressive TME. The percentage of cytotoxic T cells, which kill cancer cells, increased. By contrast, the percentage of regulatory T cells, which dampen the immune response, decreased.
The researchers used mouse models of colon and pancreatic cancer to show that siXkr8/FuOXP-NPs reduced tumour size more than FuOXP-NPs.
A novel combination
The study showed that anti-tumour activity and improvements to the TME could be achieved using this NP-based approach. This approach could be applied to various types of cancers that evade the immune response using Xkr8.
Professor Li said, “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.”