According to a recent study published in Nature Nanotechnology, scientists at the University of Pittsburgh have created cancer-fighting nanoparticles that simultaneously deliver a revolutionary immunotherapy and a chemotherapeutic medicine.
A gene that the researchers discovered was implicated in immunosuppression is silenced by the novel immunotherapy strategy. In rodent models of colon and pancreatic cancer, the therapy reduced tumor size when coupled with an already-available chemotherapeutic medication and packaged into minute nanoparticles.
The discovery of a novel therapeutic target and the development of a novel nanocarrier that is highly efficient in the selective delivery of immunotherapy and chemotherapeutic drugs are two novel aspects of our study, according to senior author Song Li, M.D., Ph.D., professor of pharmaceutical sciences at the Pitt School of Pharmacy and investigator at the UPMC Hillman Cancer Center. “This research excites me because it has a strong translational component.” “Our research indicates that there is a lot of potential, albeit we do not yet know whether our technique is effective in patients.”
Chemotherapy is a cornerstone of cancer treatment, but cancer cells that are still present might linger and lead to tumor relapse. The lipid phosphatidylserine (PS), which is typically present inside the inner layer of tumor cell membranes but migrates to the cell surface in response to chemotherapy medicines, is involved in this process. PS functions as an immunosuppressant on the surface, shielding lingering cancer cells from the immune system.
The Pitt researchers discovered that chemotherapy using the medicines fluorouracil and oxaliplatin is effective (FuOXP).
raised the amount of the protein Xkr8, which regulates how PS is distributed on cell membranes. According to this research, inhibiting Xkr8 would stop cancer cells from secreting PS to the cell surface, allowing immune cells to remove any remaining cancer cells after chemotherapy.
Yi-Nan Gong, Ph.D., assistant professor of immunology at Pitt, identified Xkr8 as a potential therapeutic target to enhance anti-tumor immune response in a separate study that was just published in Cell Reports.
Short interference RNA (siRNA), created by Li and his team, is a type of genetic code that stops the development of particular proteins, in this case, Xkr8. The next step was to direct the dual-action nanoparticles at tumors after combining siRNA and FuOXP.
However, they can reach cancer cells because tumors occasionally have poorly established blood vessels with holes that enable their passage. Nanoparticles are normally too large to traverse intact blood vessels in healthy tissue. Due to the fact that many human tumors do not have sufficiently wide pores for nanoparticles to get through, this tumor-targeting strategy is constrained.
“We sought to create a system that enables nanoparticles to cross intact blood arteries without relying on holes, like a ferry transporting passengers over a river,” said Li.
The surface of the nanoparticles was embellished with PEG and chondroitin sulfate by the researchers to create such a scaffold. By attaching to cell receptors found on both tumor blood vessels and tumor cells and extending the time they spend in the bloodstream, these substances aid nanoparticles in their ability to target tumors and avoid healthy tissue.
A considerable improvement over most other nanocarrier platforms was seen when 10% of the nanoparticles injected into mice reached their tumors. Only 0.7% of dosages of nanoparticles, on average, reach their intended targets, according to a previous survey of published research.
Compared to nanoparticles containing the chemotherapeutic drug FuOXP alone, the dual-action nanoparticles significantly inhibited the migration of immunosuppressing PS to the cell surface.
The researchers next put their platform to the test using colon and pancreatic cancer mouse models. Compared to mice given a placebo or FuOXP doses, those treated with nanoparticles containing both siRNA and FuOXP had improved tumor microenvironments with more immunosuppressive regulatory T cells and fewer cancer-fighting T cells.
Mice receiving siRNA-FuOXP nanoparticles consequently displayed a substantial reduction in tumor size as compared to those receiving only one treatment.
Li claims that the research also suggested the possibility of combining the FuOXP-siRNA nanoparticles with checkpoint inhibitors, a different class of immunotherapy. Immune checkpoints like PD-1 function as brakes on the immune system, but checkpoint inhibitors seek to disengage the brakes and support immune cells in their battle against cancer.
FuOXP nanoparticles, whether they included siRNA or not, were observed to boost PD-1 expression. However, the combination therapy dramatically improved tumor development and survival in mice when a PD-1 inhibitor was added.
The team is currently looking to validate its findings with more studies and thoroughly assess any side effects with the goal of bringing their unique medicine to the clinic.
The following scientists from Pitt or UPMC also made contributions to this study: Yuang Chen, M.S., Yixian Huang, Ph.D., Qinzhe Li, M.S., Zhangyi Luo, B.S., Ziqian Zhang, M.S., Haozhe Huang, M.S., Jingjing Sun, Ph.D., LinXinTian Zhang, B.S., and Runzi Sun, Ph.D.
