Intracellular cascade activated nanosystem for improving ER plus breast cancer therapy through attacking GSH-mediated metabolic vulnerability

Estrogen receptor-positive (ER+) breast carcinoma therapy faces the challenges of estrogen receptors heterogeneity and endocrine therapy resistance. Selectively attacking glutathione (GSH) biosynthesis which is the metabolic vulnerability of ER+ breast carcinoma could bypass conventional treatment limitations through blocking oxidative stress disorders-driven tumor cell proliferation. Herein, we developed drug-organics-inorganics self-assembled nanosystem (DFTA) with doxorubicin (DOX) as chemotherapeutic agent, ferric chloride (FeCl3) as ferroptosis inducer and tannic acid (TA) as activator of superoxide dismutase (SOD)-like reaction in intracellular cascade for the combined therapy in ER+ breast carcinoma. DFTA displayed a particle size of 106.4 +/- 0.7 nm with flat irregular nanonetwork-like shape and predominant photothermal effect produced in the assembly process. The drug release from DFTA could be triggered by photothermal excitation efficiently. ELISA analysis showed that DFTA + laser group significantly reduced intracellular GSH level through reactive oxygen species (ROS)-produced intracellular oxidative stress cascade amplification and photothermal therapy (PT)-mediated ROS production. Furthermore, in vivo antitumor efficiency evaluation showed that the tumor inhibition ratio of DFTA + laser was as high as 93.38 % even though the dosage of iron and DOX reduced by about 9 times and 1.5 times respectively. In summary, our study established a high-efficiency nanosystem based on triple combination therapy of chemotherapy, ferroptosis and PT, which might be a promising nanosystem for effective ER+ breast carcinoma therapy.