Original articles
Dong Mei, Binlong Chen, Bing He, Haibin Liu, Zhiqiang Lin, Jialiang Lin, Xiaoyan Zhang, Ning Sun, Libo Zhao, Xiaoling Wang, Qiang Zhang. Actively priming autophagic cell death with novel transferrin receptor-targeted nanomedicine for synergistic chemotherapy against breast cancer[J]. Acta Pharmaceutica Sinica B, 2019, 9(5): 1061-1077

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
a Clinical Research Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China;
b Key Laboratory of Molecular Pharmaceutics, New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China;
c Department of General Surgery, China-Japan Friendship Hospital, Beijing 100029, China;
d Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
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 receptor (TfR). Cytotoxic paclitaxel (PTX)-loaded micelle (7pep-M-PTX) was regarded as chemotherapeutic 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-MPTX used in combination provided enhanced efficacy through induction of both apoptosis-and mitochondria-associated autophagic cell death. Together, our findings suggested that the targeted excess autophagy may provide a rational strategy to improve therapeutic outcome of breast cancer, and simultaneous induction of ACD and apoptosis may be a promising anticancer modality.
Key words:    Autophagic cell death    Combination therapy    Targeted delivery    Rapamycin    Breast cancer    Transferrin receptor    Mitophagy    Nanomedicines    7pep   
Received: 2019-02-18     Revised: 2019-03-08
DOI: 10.1016/j.apsb.2019.03.006
Funds: This research was supported by the National Natural Science Foundation of China (81690264), Key Project from the Ministry of Science and Technology (Grant No. 2018ZX09721003), Scientific Research Incubation Fund of Beijing Children's Hospital, Capital Medical University (Grant No. GPY201711, China).
Corresponding author: Xiaoling Wang, Qiang Zhang     Email:eyjdb6380@163.com;zqdodo@bjmu.edu.cn
Author description:
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Dong Mei
Binlong Chen
Bing He
Haibin Liu
Zhiqiang Lin
Jialiang Lin
Xiaoyan Zhang
Ning Sun
Libo Zhao
Xiaoling Wang
Qiang Zhang

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