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    r> *Corresponding authors.
    Peer review under responsibility of Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association.
    2211-3835/ª 2019 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (
    Please cite this article as: Mei D et al., Actively priming autophagic cell death with novel transferrin receptor-targeted nanomedicine for synergistic chemotherapy against breast cancer, Acta Pharmaceutica Sinica B,
    + MODEL
    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 simul-taneous induction of ACD and apoptosis may be a promising anticancer modality.
    ª 2019 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND li-
    cense (
    1. Introduction
    Cancer is the leading cause of death around the world, and chemotherapy is the most widely used treatment in clinic1. However, the efficacy of monotherapy is usually limited in clinic due to the complexity and refractory of cancer. Whether it SC 236 is treated by conventional cytotoxic drugs or molecularly-targeted therapeutics, the drug resistance, insufficient curative effect and tumor relapse are still the huge challenges2,3. With the increased understanding of the mechanisms underlying the compromised therapeutic efficacy of monotherapy, combination therapy with two or more therapeutic agents generally acting on multiple therapeutic targets, or one increasing the sensitivity of SC 236 tumor cells to another one, has increasingly become a standard practice in clinic4,5. In particular, as more and more regulators of signaling proteins or pathways which play key roles in oncogenic trans-formation and drug resistance are identified, the combined stra-tegies of these regulators with the current chemotherapeutics are being studied extensively for cancer treatment6,7.
    Novel combinations of small molecularly targeted agents with chemotherapy, have gained increasing attention in research that aims to overcome drug resistance and tumor heterogeneity for highly effective cancer regimens. Rapamycin (RAP), a mamma-lian target of rapamycin (mTOR) inhibitors, was developed as a potential anticancer drug, including lung, cervix, colon and breast cell carcinomas8. Studies have found that RAP or its derivatives enhanced the antitumor efficacy of taxane chemotherapeutic agents (e.g., paclitaxel (PTX)) in many clinical trials9,10 by tar-geting the mTOR protein, which is centrally involved in angio-genesis, cell survival, proliferation and metabolism11e14. The currently reported synergistic anti-tumor mechanism of combined RAP or its derivatives with PTX mainly involves the anti-
    angiogenesis effect of RAP and its direct inhibition of mTOR in tumor development15,16.
    In addition, RAP is the most commonly used agent to induce autophagy. Recent evidence has indicated that tumor suppression
    following RAP treatment is linked to the induction of autophagic cell death (ACD)17,18. Autophagy is a highly regulated process
    that degrades or recycles bulk cytoplasmic constituents through lysosome-based pathway, resulting in the formation of a double-membranous structure, which is termed as an autophagosome in eukaryotic cells. The autophagic process is robustly upregulated in response to cellular stress, and it is known to be involved in a multitude of cellular processes including immunity, programmed cell death, the selective degradation of organelles, tumor, aging and numerous neurodegenerative conditions, while its precise role in the development of tumors is ambiguous19,20. Although some evidence suggested that autophagy promotes cell survival under