J Control Release 2019 Jul 23;309:145-157. Epub 2019 Jul 23.
State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address:
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 (FeCl) 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.