Interference With Redox Homeostasis Through a G6PD-Targeting Self-Assembled Hydrogel for the Enhancement of Sonodynamic Therapy in Breast Cancer

Abstract

Sonodynamics has emerged as a new potential therapy for breast cancer in recent years. However, GSH-mediated redox systems in cancer cells make them tolerable to oxidative stress-related therapy. Herein, in this study, with G6PD, the gatekeeper enzyme of the pentose phosphate pathway, as the regulative target, a self-assembled thermosensitive chitosan-pluronic hydrogel coloaded with ICG (sono-sensitive agent) and RRx-001 (IR@CPGel) was successfully prepared to enhance SDT through interference with redox homeostasis. Both <i>in vitro</i> and <i>in vivo</i> antitumor investigations verified that when integrated with sonodynamic therapy applied in breast cancer treatment, local administration of IR@CPgel could enhance ROS generation under LIFU irradiation and trigger the intrinsic apoptotic pathway of cancer cells, thus effectively inhibiting tumor growth in a safe manner. Moreover, RRx-001 may interfere with redox homeostasis in cancer cells by downregulating G6PD expression. Due to this redox imbalance, proapoptotic signals, such as P21 and P53, were enhanced, and metastasis-related signals, including MMP-2, ZEB1 and HIF-1α, were effectively reduced. Taken together, this work aimed to enhance the efficacy of sonodynamic therapy through local administration of self-assembled IR@CPGel to interfere with redox homeostasis and thus amplify the oxidative stress microenvironment in tumor tissues. In a word, this work provides a new strategy for the SDT enhancement in breast cancer therapy.