Thermosensitive micellar hydrogel for enhanced anticancer therapy through redox modulation mediated combinational effects

Abstract

Cancer is increasingly viewed as an eco-system, a community in which tumor cells cooperate with other tumor cells and host cells in their microenvironment. The improved understanding of the intricate relationships in this eco-system has led to revolutionary treatments, which have evolved from relatively nonspecific cytotoxic agents to selective, mechanism-based therapeutics. Herein, from the view of dynamic equilibrium, a synergistic intracellular redox-regulation therapeutic strategy was proposed, in which combinational treatment of chemotherapeutic agents and ROS-elimination inhibitors was expected to effectively kill cancer cells and overcome redox adaptation mechanism associated drug resistance. To this end, a thermosensitive micellar hydrogel was prepared for co-delivery of nanomedicines in situ, which was capable of encapsulating and delivering multiple drugs with diverse therapeutic properties while maintaining the controlled synergistic ratio. Firstly, fluorescence resonance energy transfer (FRET) technology was adopted to track the real-time spatial pattern of drug presentation at a molecular level in this micellar hydrogel. Results suggested that the drug encapsulation in this micellar hydrogel platform proved to be a dynamic equilibrium process, during which free drug movement, drug exchange or penetration between micelles could occur. Furthermore, doxorubicin (DOX) and Zn(II) protoporphyrin IX (ZnPP) were used as the model chemotherapeutant and HO-1 inhibitor, respectively. In vitro and in vivo evaluation demonstrated that the intracellular redox-regulation mediated synergistic advantages of both two types of drugs translated into improved therapeutic outcomes. Consequently, such a thermosensitive micellar hydrogel formulation, which enabled precise control over the dosage and ratio of combination therapeutic agents to obtain the desired therapeutic effect with a single drug administration, holds great potential for spatiotemporal delivery of multiple bioactive agents for sustained combination therapy.