Glycyrrhizic Acid-Based Liposome for Tumor-Targeted Delivery of Cantharidin

Cantharidin (CTD), an effective ingredient derived from poisonous traditional Chinese medicine Mylabris, shows unique efficacy against hepatocellular carcinoma (HCC), but severe toxicity hinders its clinical application. Liposomes (LPs) are considered to be a platform for the effective delivery of chemotherapeutic agents. Nevertheless, the application of cholesterol, which is usually used to stabilize the structure of LPs, has been compromised due to various drawbacks. Glycyrrhizic acid (GA) has the ability to improve the properties of the phospholipid bilayer in addition to its targeting and hepatoprotective effects. Here, we develop a GA LP loaded with CTD (CTD–GA–LP) utilizing GA as a cholesterol replacement to effectively overcome the obstacles faced by common LPs and to enhance the efficacy of CTD and reduce its toxicity. In the study, CTD–GA–LP was prepared by the ethanol injection method and comprised a homogeneous spherical shape with an evenly distributed particle size, showing a particle size and polydispersity index of 76.12 ± 4.01 nm and 0.18 ± 0.02, respectively. CTD–GA–LP exhibited a better drug loading capacity and stability than CTD–C–LP. An in vitro study showed that CTD–GA–LP can selectively target tumor cells and significantly improve cellular absorption by the GA-receptor-mediated endocytosis pathway to achieve active targeted delivery of drugs. Compared with CTD–C–LP, CTD–GA–LP exhibited notably higher toxicity to the growth of HepG2 cells and low toxicity to L-02 hepatocytes. Using a H22 tumor-bearing mice model, CTD–GA–LP was proved to be able to promote the accumulation of CTD in the tumor tissue and possessed the most pronounced tumor inhibitory rate. Also, CTD–GA–LP reduced the accumulation of CTD in normal organs and prolonged the survival time of tumor-bearing mice. In conclusion, CTD–GA–LP provides an attractive and potential strategy for the treatment of HCC and is very useful for improving the effectiveness and safety of CTD.