Boosting synergism of chemo-and immuno-therapies via switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis by bisphosphonate coordination lipid nanogranules

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外文摘要：Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted drugs.It is critical to inspire new potential to remodel the value of this classical therapeutic strategy.Here,we fabricate bisphospho-nate coordination lipid nanogranules(BC-LNPs)and load paclitaxel(PTX)to boost the chemo-and immuno-therapeutic synergism of cytotoxic drugs.Alendronate in BC-LNPs@PTX,a bisphosphonate to block mevalonate metabolism,works as both the structure and drug constituent in nanogranules,where alendronate coordinated with calcium ions to form the particle core.The synergy of alendronate enhances the efficacy of paclitaxel,suppresses tumor metastasis,and alters the cytotoxic mechanism.Differing from the paclitaxel-induced apoptosis,the involvement of alendronate inhibits the mevalonate meta-bolism,changes the mitochondrial morphology,disturbs the redox homeostasis,and causes the accumulation of mitochondrial ROS and lethal lipid peroxides(LPO).These factors finally trigger the ferroptosis of tumor cells,an immunogenic cell death mode,which remodels the suppressive tumor im-mune microenvironment and synergizes with immunotherapy.Therefore,by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis,BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.

外文关键词：

Bisphosphonate coordination lipid nanogranulesFerroptosisMevalonate metabolismMitochondrial metabolismNano-systematic biology

作者：

Ge Song、Minghui Li、Shumin Fan、Mengmeng Qiri、Bin Shao、Wenbing Dai、Hua Zhang、Xueqing Wang、Bing He、Qiang Zhang

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作者单位：

Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems,School of Pharmaceutical Sciences,Peking University,Beijing 100191,China

State Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking University,Beijing 100191,China

Department of Medical Oncology,Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education),Peking University Cancer Hospital,Beijing 100142,China

基金：

National Key Research and Development Program,ChinaNatural Science Foundation of Beijing Municipality,ChinaAI+Health Collaborative Innovation Cultivation Project,ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of China

项目编号：

2022YFA1206100L212013Z2111000035210028207378681872809U20A2041281821004

出版年：

2024

DOI：

10.1016/j.apsb.2023.08.029

药学学报(英文版)

CSTPCD

ISSN：

年,卷(期)：2024.14(2)

参考文献量47