Construction of dual-targeted liposomes loaded with celastrol and their application in treating intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is a rare malignant tumor with limited treatment options. Celastrol (Cela) shows potential treatment for ICC, but its clinical use is hindered by poor water solubility and toxic side effects. To address these challenges and enhance its anti-tumor efficacy, we developed hyaluronic acid (HA)-coated triphenylphosphine complex-modified liposomes (HCTL) for accurate delivery of Cela to tumor cell mitochondria.HCTL enhances Cela's water solubility and demonstrates a high rate of encapsulation, stability, and sustained drug release behavior. Moreover, HCTL exhibits outstanding anti-ICC efficacy by efficiently inducing apoptosis in ICC cells via the mitochondrial pathway due to its precise targeting capabilities. In an in-situ ICC mouse model activated by hydrodynamic transfection of AKT and Yap, HCTL downregulates tumor-associated proliferative indices, attenuates the severity of liver injury and modulates the tumor microenvironment. Importantly, HCTL overcomes systemic toxicity associated with Cela. To sum up, HCTL is a potentially effective drug delivery system for ICC treatment.