Actively priming autophagic cell death with novel transferrin receptor-targeted nanomedicine for synergistic chemotherapy against breast cancer.
10.1016/j.apsb.2019.03.006
- Author:
Dong MEI
1
;
Binlong CHEN
2
;
Bing HE
2
;
Haibin LIU
3
;
Zhiqiang LIN
4
;
Jialiang LIN
2
;
Xiaoyan ZHANG
1
;
Ning SUN
1
;
Libo ZHAO
1
;
Xiaoling WANG
1
;
Qiang ZHANG
2
Author Information
1. Clinical Research Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.
2. Key Laboratory of Molecular Pharmaceutics, New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
3. Department of General Surgery, China-Japan Friendship Hospital, Beijing 100029, China.
4. Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
- Publication Type:Journal Article
- Keywords:
7pep;
Autophagic cell death;
Breast cancer;
Combination therapy;
Mitophagy;
Nanomedicines;
Rapamycin;
Targeted delivery;
Transferrin receptor
- From:
Acta Pharmaceutica Sinica B
2019;9(5):1061-1077
- CountryChina
- Language:English
-
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 and more tumor accumulation of micelles , 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.
