Amplification of tumor oxidative stresses with Shikonin-Fe(II) liposomal nanomedicine for enhanced anticancer treatment

Abstract

Tumoral cell apoptosis and necroptosis could be accelerated by further amplified intracellular oxidative stress, which could be enhanced through the ferrous-based intracellular Fenton reaction. Shikonin, a necroptosis inducer and anticancer chemotherapeutic drug, has been reported to be able to produce the intracellular reactive species (ROS) in several types of tumor cells, facilitating oxidative stress increase by coordination with ferrous. A functional complex (Shik-Fe(II)) served not only as the catalyst of Fenton reaction but also as the ROS producer was prepared in this work. However, the formulated Shik-Fe(II) exhibited the poor water solubility alongside with the fast clearance rate, resulting in the limited application. Herein, Shik-Fe(II) was encapsulated in the stealth liposomal carrier to overcome the poor water solubility of Shik-Fe(II) and form the functional lipid nanomedicine Shik-Fe(II)@Lip. After the internalization of Shik-Fe(II)@Lip by neuroblastoma cells, the intracellular oxidative stress could be dramatically enhanced by the increased level of ROS as well as the cytotoxic hydroxyl radicals (·OH) generating from Fe(II)-mediated Fenton reaction, ultimately resulting in the advanced therapeutic effect. Thus, this work presents the preparation of functional Shik-Fe(II)@Lip as an effective anticancer formulation with both chemotherapeutic effect and the remarkable intracellular oxidative stress amplification capability for clinical application.