Induction of Ferroptosis by Dual-Targeting pH-Responsive Nanomicelles in the Treatment of Tamoxifen-Resistant Breast Cancer

Tamoxifen (TAM) is a front-line option for the treatment of estrogen receptor (ER)-positive breast cancers, but TAM resistance often presents a significant challenge. The mechanism underlying this resistance is complex, but it mainly involves metabolic differences and increased expression of drug-resistant proteins, such as hexokinase 2 (HK2). In this study, a dual targeting (ER and CD44 receptor) nano hybrid micelle system (HTT@3-BP-CL) was designed. It was composed of the hyaluronic acid ester of the TAM active metabolite 4-hydroxytamoxifen (4-OH-TAM) and d-α-tocopheryl polyethylene glycol succinate and was loaded with the HK2 inhibitor prodrug 3-bromopyruvate cholesteryl ester (3-BP-CL). We reasoned that the use of 4-OH-TAM would minimize inconsistent efficacy caused by individual metabolic differences and that the 3-BP released in the acidic tumor microenvironment would inhibit the production of ATP and NADPH. We found that HTT@3-BP-CL induces ferroptosis of MCF-7/TAM cells through a mechanism that involves inhibition of HK2 and downstream effects on oxidative stress via decreased reduced glutathione and glutathione peroxidase activity. Off-target effects were minimized through dual targeting and responsiveness of the esterified prodrugs to the acidic tumor microenvironment. HTT@3-BP-CL exhibits an efficient antitumor effect with low toxicity in TAM-resistant breast cancer models in vitro and in vivo. Our research provides a strategy for TAM-resistant breast cancer therapy.