To enhance the therapeutic efficacy and safety of triple-negative breast cancer (TNBC) treatment, we developed a hypoxia-responsive drug delivery system utilizing digoxin (DIG) to inhibit HIF-1α and sensitize TNBC to doxorubicin (DOX). DIG, a cardiac steroid with a well-characterized pharmacological mechanism, was encapsulated in micelles composed of methoxy-polyethylene glycol (mPEG) and poly(lactic acid) (PLA) copolymers, incorporating an azobenzene (AZO) trigger for hypoxia-sensitive drug release. The loading ratio of DOX to DIG was optimized based on DIG's minimum effective dose. In vitro and in vivo studies demonstrated that the micelles efficiently delivered their payload to hypoxic tumor regions, enabling rapid drug release. DIG-mediated HIF-1α inhibition enhanced TNBC sensitivity to DOX, leading to significant suppression of both primary tumor growth and pulmonary metastasis. This study presents a promising and clinically feasible strategy for TNBC and other hypoxia-driven malignancies.
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