1. Actively priming autophagic cell death with novel transferrin receptor-targeted nanomedicine for synergistic chemotherapy against breast cancer.
- Author
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Mei, Dong, Chen, Binlong, He, Bing, Liu, Haibin, Lin, Zhiqiang, Lin, Jialiang, Zhang, Xiaoyan, Sun, Ning, Zhao, Libo, Wang, Xiaoling, and Zhang, Qiang
- Subjects
CANCER chemotherapy ,CELL death ,TRANSFERRIN receptors ,NANOMEDICINE ,COMBINATION drug therapy - 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 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-M-PTX 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. This study demonstrates the improved therapeutic efficacy and its mechanism of transferrin receptor-targeted nanomedicine against breast tumor. Through ligand-receptor mediated active targeting and inducing massive accumulation of autophagic vesicles, combination chemotherapy that acted on both autophagic cell death (ACD) and apoptosis provided enhanced efficacy and reduced toxicity. Image 1 [ABSTRACT FROM AUTHOR]
- Published
- 2019
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