Abstract
Mitochondrial-targeting therapy was considered to be a promising approach for the efficient treatment of cancer while positive charge induced nonspecific cytotoxicity severely limits its application. To overcome this drawback, a novel mitochondria targeted conjugate triphenylphosphine-docetaxel (TD) has been synthesized successfully and incorporated it into liposomes (EPSLP/TD), which possessed excellent pH-sensitive characteristic, EphA 10 mediated active targetability as well as mitochondria-targeting capability. EPSLP/TD was characterized to have a small particle size, high-encapsulation efficiency and excellent pH-sensitive characteristic. Compared with DTX-loaded liposomes (EPSLP/DTX), EPSLP/TD possessed higher cytotoxicity against MCF-7 cell line. Mitochondrial-targeting assay demonstrated mitochondria-targeting moiety triphenylphosphine (TPP) could efficiently deliver DTX to mitochondria. Western immunoblotting assay indicated that EPSLP/TD could efficiently deliver antitumor drug to mitochondria and induce cell apoptosis via mitochondria-mediated apoptosis pathway. In vivo antitumor study demonstrated EPSLP/TD owed excellent in vivo antitumor activity. Histological assay demonstrated EPSLP/TD showed strongly apoptosis inducing effect, anti-proliferation effect and anti-angiogenesis effect. This work investigated the potential of hierarchical targeting pH-sensitive liposomes is a suitable carrier to activate mitochondria-mediated apoptosis pathway for cancer therapy.
Highlights
Cancer is a great challenge to human’s health over last few decades (Malhi et al, 2012; Noh et al, 2015; Perez-Herrero and Fernandez-Medarde, 2015; Yang et al, 2015; Abdel Aziz et al, 2016)
We can hypothesis that in acidic tumor microenvironment, Schiff base bond would hydrolyze and EphA 10-Polyethylene glycol (PEG) outer shell would be removed from the surface of the liposomes, followed by the exposure of the positive charge. All these results indicated that EPSLP/TD showed pHresponsive capability via the cleavage of pH-sensitive bond
Expression of Bax protein increased in different degree for different drugtreated groups and Bcl-2 expression of different groups decreased, as well. These results demonstrated that cell apoptosis was depended on the mitochondria-mediated cell apoptosis pathway
Summary
Cancer is a great challenge to human’s health over last few decades (Malhi et al, 2012; Noh et al, 2015; Perez-Herrero and Fernandez-Medarde, 2015; Yang et al, 2015; Abdel Aziz et al, 2016). Among all of the treatment against cancer, chemotherapy is considered to be one of the most widely used application in clinical (Wang et al, 2011; Li et al, 2013a; Ma et al, 2013; Zhou et al, 2013). Target drug delivery offers a potential strategy for the chemotherapy. Antitumor drugs kill tumor cells by two basic approaches. One is to kill cancer cells by directly exposing them to toxic chemicals. Another is to induce the suicide of cancer cells apoptosis (Zhou et al, 2013). There are two major apoptosis pathways: extrinsic and intrinsic pathways, which both activate the caspases. The extrinsic is triggered at plasma membrane through activating the death receptors
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