Actively priming autophagic cell death with novel transferrin receptor-targeted nanomedicine for synergistic chemotherapy against breast cancer

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.

Design, synthesis, and biological evaluation of quinazolin-4(3H)-one derivatives co-targeting poly(ADP-ribose) polymerase-1 and bromodomain containing protein 4 for breast cancer therapy

“…According to the statistics of international cancer research institute, breast cancer has become the highest incidence of cancer among women in the world 5 . Currently, the main treatment for BC patients is chemotherapy with small-molecule drugs in addition to radiotherapy and surgery 6 , 7 , 8 . As shown in Fig.…”

Bone-seeking nanoplatform co-delivering cisplatin and zoledronate for synergistic therapy of breast cancer bone metastasis and bone resorption

“…The combination index (CI) was calculated using Eq. (3) 34 , 35 : where D 1 and D 2 are the doses of drug 1 and drug 2 in combination that produce a specific drug effect ( e . g ., 50% inhibitory concentration), while D m1 and D m2 are drug concentrations at which the same drug effect achieved when dosed individually.…”

Exploring new Horizons in overcoming P-glycoprotein-mediated multidrug-resistant breast cancer via nanoscale drug delivery platforms

“…(2016) 7pep Rapamycin and PTX co-loaded DSPE-PEG micelles Superior MCF-7 BC cell uptake was observed, thus leading to higher antitumor and autophagic cell death in vitro and in vivo . Mei et al. (2019) 7pep Micelles developed from podophyllotoxin, methoxy-PEG and 7 pep conjugate Targeted delivery improved the maximum tolerated dose of toxic podophyllotoxin by 5.3-fold in vivo .…”