Gambogic acid-loaded transferrin-modified liposomes enhancing potent ferroptosis in breast cancer.

Breast cancer (BC), the most common cancer in women, is closely related to ferroptosis, which is an iron-dependent form of cell death. Gambogic acid (GA), the main active ingredient extracted from the dry resin secreted by Garcinia cambogia, can effectively induce ferroptosis in tumor cells. However, its application is limited by poor water solubility, short half-life, and vascular irritation. Moreover, the sensitivity of cells to ferroptosis is positively correlated with the concentration of intracellular iron ions, which based on transferrin (Tf)-Tf receptor (TfR) pathway. Increasing intracellular iron ions within tumor cells may enhance GA-induced ferroptosis. Based on the high expression of TfR in tumor cells, Tf can be both a tumor-target modification and an Fe3+ carrier. Therefore, GA-loaded Tf-modified liposomes (GA@Tf-Lip) with pH-responsive properties were developed. GA@Tf-Lip increased the intracellular iron ion content of MCF-7 cells, promoted the Fenton reaction to increase the level of ROS, downregulated the GSH content, and accelerated lipid peroxide accumulation. The distribution of the formulation by in vivo imaging experiments showed that the prepared GA@Tf-Lip had a higher drug accumulation at tumor sites and exhibited a good antitumor effect by promoting ferroptosis. Overall, GA@Tf-Lip exerted a good anti-BC effect, which is expected to provide a new strategy for the treatment of BC and the clinical transformation of GA.