KINGSTON, R.I. — Aug. 7, 2023 — Nearly 30 percent of the cases of hepatocellular carcinoma, the fastest-growing cause of cancer-related death in the world, have been attributed to chronic alcohol liver disease. Heavy alcohol consumption leads to fatty liver, hepatitis and eventually cirrhosis, which increases the risk for cancer development. Despite the prevalence of the condition, treatments against alcohol liver disease and associated fibrosis have proven largely unsuccessful due to the poor pharmacokinetics, toxicity and the difficulty of targeting therapies to specific liver cells.
University of Rhode Island College of Pharmacy Associate Professor Jyothi Menon is working to overcome these barriers to treatment using nanoparticles that can specifically target liver cells responsible for hepatic fibrosis, enhance the penetration of drugs into the fibrotic liver tissue, deliver needed medications, and facilitate the timed release of the therapeutics. Her efforts are supported by a grant from the National Institutes of Health’s National Cancer Institute and the Biden Cancer Moonshot, a program launched by the White House last year “to support early-career researchers and help build a cancer research workforce that better represents the diversity of America.”
Using nanoparticles created from polymers and lipids in her lab, Menon is specifically targeting liver macrophages that play a major role in the liver’s response to stresses including alcohol, to suppress cell signaling responsible for hepatocellular carcinoma (HCC) development. The nanoparticles—roughly 1000 times smaller than the diameter of a human hair, small enough to navigate through biological barriers and protect their cargo from degradation—are designed to specifically target and activate Gpbar1, a protein expressed by the liver’s Kupffer cells, leading to suppression of signaling responsible for liver inflammation and fibrosis.
“Usually with liver fibrosis and cirrhosis, researchers have explored the therapeutic targeting of hepatocytes, which makes up about 70 percent of the cells in the liver,” Menon said. “Kupffer cell targeting is something not a lot of people have explored, despite its role in liver disease initiation and development. Most drugs are inherently non-specific and can go anywhere in the body. In this research, we propose to deliver the nanoparticles intravenously, following which they will arrive in the liver, and recognize and bind to the proteins on the Kupffer cells.”
In addition to activating cell surface proteins, nanoparticles can be used as a carrier system to deliver anti-fibrotic and anti-cancer therapies to the liver. The nanoparticles can be designed to release the drug in a sustained manner over time.
The focus of Menon’s project is on treating inflammation of the liver caused specifically by alcohol liver disease. But the treatment could be applied to liver inflammation from other causes, including a high-fat diet, drug use and even some prescribed medications.
“Liver disease in general is rising in incidence, not just in adults, but in children as well. The global burden of liver disease is expected to increase by at least two-to-three-fold in the next 10 years,” Menon said. “So it is important for us to develop preventative interventions that can lower the chances of patients with advanced liver disease from developing HCC. Right now, my focus is on alcohol-associated fibrosis and its progression, but I hope to build on our findings in this project to develop better therapeutic interventions against other chronic liver diseases including HCC.”