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  • br Jagsi R Hawley ST Griffith KA

    2020-03-24


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    Acta Pharmaceutica Sinica B xxxx;xxx(xxx):xxx
    Chinese Pharmaceutical Association
    Institute of Materia Medica, Chinese Academy of Medical Sciences
    Acta Pharmaceutica Sinica B
    ORIGINAL ARTICLE
    Actively priming autophagic cell death with novel transferrin receptor-targeted nanomedicine for synergistic chemotherapy against breast cancer
    Dong Meia,b, Binlong Chenb, Bing Heb, Haibin Liuc, Zhiqiang Lind, Jialiang Linb, Xiaoyan Zhanga, Ning Suna, Libo Zhaoa, Xiaoling Wanga,*, Qiang Zhangb,*
    aClinical Research Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China
    bKey Laboratory of Molecular Pharmaceutics, New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China cDepartment of General Surgery, China-Japan Friendship Hospital, Beijing 100029, China dInstitute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
    KEY WORDS
    Autophagic cell death; Combination therapy; Targeted delivery; Rapamycin; Breast cancer;
    Transferrin receptor;
    Mitophagy;
    Nanomedicines;
    7pep
    Abstract Recently, considerable attention in the field of cancer therapy has been focused on the mammalian rapamycin target (mTOR), inhibition of which could result in autophagic cell death (ACD). Though novel combination chemotherapy of autophagy inducers with chemotherapeutic agents is extensively investigated, nanomedicine-based combination therapy for ACD remains in infancy. In attempt to actively trigger ACD for synergistic chemotherapy, here we incorporated autophagy inducer rapamycin (RAP) into 7pep-modified PEG-DSPE polymer micelles (7pep-M-RAP) to specifically target and efficiently priming ACD of MCF-7 human breast cancer cells with high expression of transferrin re-ceptor (TfR). Cytotoxic paclitaxel (PTX)-loaded micelle (7pep-M-PTX) was regarded as chemothera-peutic drug model. We discovered that with superior intracellular uptake in vitro and more tumor accumulation of micelles in vivo, 7pep-M-RAP exhibited excellent autophagy induction and synergistic antitumor efficacy with 7pep-M-PTX. Mechanism study further revealed that 7pep-M-RAP and 7pep-M-PTX used in combination provided enhanced efficacy through induction of both apoptosis- and