{"title":"Hypoxia-Targeted Responsive Delivery of Doxorubicin and Digoxin for Synergistic Treatment of Triple-Negative Breast Cancer.","authors":"Lingyan Weng, Min Zhao, Zhongping Chen, Li Zhu","doi":"10.1021/acs.molpharmaceut.4c01325","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"2142-2158"},"PeriodicalIF":4.5000,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Pharmaceutics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acs.molpharmaceut.4c01325","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/3/9 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
Abstract
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.
期刊介绍：
Molecular Pharmaceutics publishes the results of original research that contributes significantly to the molecular mechanistic understanding of drug delivery and drug delivery systems. The journal encourages contributions describing research at the interface of drug discovery and drug development.
Scientific areas within the scope of the journal include physical and pharmaceutical chemistry, biochemistry and biophysics, molecular and cellular biology, and polymer and materials science as they relate to drug and drug delivery system efficacy. Mechanistic Drug Delivery and Drug Targeting research on modulating activity and efficacy of a drug or drug product is within the scope of Molecular Pharmaceutics. Theoretical and experimental peer-reviewed research articles, communications, reviews, and perspectives are welcomed.
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