Esterase-activated fluorescent prodrug for targeted early diagnosis and treatment of hepatic fibrosis

Hepatic fibrosis (HF) is a progressive scarring process primarily caused by chronic inflammation and injury, leading to serious complications such as liver failure, cirrhosis, and hepatocellular carcinoma. Early diagnosis and effective medication can prevent complications. In addition to the lack of methods for early diagnosis, therapeutic drugs cannot be delivered in a controlled manner, resulting in uneven biological distribution of the drug and significant side effects; ultimately, the ideal therapeutic effect cannot be achieved. Some recent studies have revealed that esterase levels are significantly abnormal during the early stages of various types of liver diseases. Therefore, we hope to develop an esterase-activated drug delivery fluorescence system to achieve targeted diagnosis and visual drug delivery of HF. In this work, a fluorescent prodrug (HC-Cl-UDCA) was designed by linking the near-infrared (NIR) chlorinated hemicyanine fluorophore to ursodeoxycholic acid (first-line drug for liver disease) via an ester bond. HC-Cl-UDCA can be rapidly activated ( by esterase in the liver to release a NIR fluorescence signal and the therapeutic drug UDCA. Most importantly, we achieved early diagnosis in a one-week HF mouse model and demonstrated excellent drug retention capacity in the liver. To our knowledge, this is the first esterase-driven fluorescent prodrug for HF therapy.