Abstract:
:Cancer cell metabolism is quite different from normal cells. Targeting cancer metabolism and untuning the tumor metabolic machine has emerged as a promising strategy for cancer therapy. We have developed a multi-functional Re-dca conjugate (Re-dca 2) by conjugating the metabolic modulator dichloroacetate (DCA) to mitochondria-targeted rhenium(I) complex, allowing its efficient penetration into cancer cells and selective accumulation in mitochondria, thus achieving the cancer cell metabolism reversal from glycolysis to glucose oxidation at pharmacologically relevant DCA doses. Mechanism studies confirm the inhibition effect of Re-dca 2 on the activity of pyruvate dehydrogenase kinase (PDK) and capture the metabolic reversal window in Re-dca 2 treated NCI-1229 cells at the early stage of drug treatment, resulting in selective killing of malignant cells cocultured with normal cells, significant inhibition of cancer cell metastasis and invasion, as well as excellent anti-angiogenesis activities in zebrafish embryos. By comparison, DCA-free Re(I) analogue is also investigated under the same conditions. Although this analogue also exhibits cytotoxicity due to the Re(I) core, metabolic reversal is not induced by this analogue and its anti-metastasis activity is much lower than Re-dca 2, indicating the synergistic effect of Re(I) core and DCA moiety on cancer therapy. In vivo anti-cancer investigations also indicate that the mitochondria-targeted Re-dca 2 can effectively inhibit the tumor growth without affecting the body weight of nude mice, and the therapeutic effect is much better than the DCA-free Re(I) analogue 2a. Simultaneously, the O2-sensitive phosphorescent lifetimes of Re-dca 2 can be utilized for PLIM imaging of intracellular oxygen consumption, thus reflecting the Re-dca 2 induced glycolysis-to-glucose oxidation reversal at the early drug treatment stage. The excellent phosphorescence of Re-dca 2 can also be utilized for real-time tracking of mitochondrial morphological changes during treatment. In a word, rational design of phosphorescent metallodrug and metabolic modulator conjugates for synergistic treatment is a promising strategy for simultaneous untuning and tracking tumor metabolic machine, thus providing new clues for cancer therapy and mechanisms.
journal_name
Biomaterialsjournal_title
Biomaterialsauthors
Yang J,Cao Q,Zhang H,Hao L,Zhou D,Gan Z,Li Z,Tong YX,Ji LN,Mao ZWdoi
10.1016/j.biomaterials.2018.05.040subject
Has Abstractpub_date
2018-09-01 00:00:00pages
94-105eissn
0142-9612issn
1878-5905pii
S0142-9612(18)30391-0journal_volume
176pub_type
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