Recently, considerable attention in the field of cancer therapy has been focused on the mammalian rapamycin target(m TOR), inhibition of which could result in autophagic cell death(ACD). Though novel combination chemo...Recently, considerable attention in the field of cancer therapy has been focused on the mammalian rapamycin target(m TOR), 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 7 pep-modified PEG-DSPE polymer micelles(7 pep-M-RAP) to specifically target and efficiently priming ACD of MCF-7 human breast cancer cells with high expression of transferrin receptor(Tf R). Cytotoxic paclitaxel(PTX)-loaded micelle(7 pep-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, 7 pep-M-RAP exhibited excellent autophagy induction and synergistic antitumor efficacy with 7 pep-M-PTX. Mechanism study further revealed that 7 pep-M-RAP and 7 pep-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.展开更多
基金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)
文摘Recently, considerable attention in the field of cancer therapy has been focused on the mammalian rapamycin target(m TOR), 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 7 pep-modified PEG-DSPE polymer micelles(7 pep-M-RAP) to specifically target and efficiently priming ACD of MCF-7 human breast cancer cells with high expression of transferrin receptor(Tf R). Cytotoxic paclitaxel(PTX)-loaded micelle(7 pep-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, 7 pep-M-RAP exhibited excellent autophagy induction and synergistic antitumor efficacy with 7 pep-M-PTX. Mechanism study further revealed that 7 pep-M-RAP and 7 pep-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.
