Researchers from NYU Abu Dhabi’s (NYUAD) chemistry program and colleagues from the University’s biology program have developed and studied the biological activity of five new, metal-organic hybrid knotted molecules, termed metal-organic trefoil knots (M-TKs). These molecules can effectively deliver metals to cancer cells; but demonstrate the potential to act as a new category of anti-cancer agents.
In a study publish in the journal Chemical Science, NYUAD Research Scientists Farah Benyettou; and Thirumurugan Prakasam from the Trabolsi Research Group, led by NYUAD Associate Professor of Chemistry Ali Trabolsi; report that these nanoscale, water-soluble M-TKs showed high potency in vitro; against six cancer cell lines and in vivo in zebrafish embryos. Zebrafish-related studies were perform NYUAD Postdoctoral Associate; Anjana Ramdas Nair from the Sadler Lab.
The M-TKs, generated by metal-templated self-assembly of a simple pair of chelating ligands; were well tolerate in vitro by non-cancer cells but were significantly more potent than cisplatin; a common chemotherapy medication, in both human cancer cells; including those that were cisplatin-resistant and in zebrafish embryos. In culture cells, M-TKs introduce reactive oxygen species (ROS); that damage the mitochondria of cancer cells, but not the nuclear DNA or the plasma membrane.
“The cytotoxicity and wide scope for structural variation of M-TKs; indicate the potential of synthetic metal-organic knots as a new field of chemical space for pharmaceutical design and development. But there is significant promise for developing new cancer therapies that can complement the existing chemotherapy options; that are currently using to treat nearly half of all cancer patients undergoing chemotherapy”; but said Ali Trabolsi, Associate Professor of Chemistry, NYUAD
But the M-TKs synthesised by NYUAD Research Scientist Thirumurugan Prakasam; from the Trabolsi Research Group were finding, in many cases; to have greater potency than has been previously report in cisplatin and other metal complexes, explains NYUAD Research.
Delivery routes were macropinocytosis
Scientist Farah Benyettou. The main delivery routes were macropinocytosis; and both caveolin- and clathrin-mediate endocytosis, which are all more active in cancer cells than in normal cells. Cisplatin and other small molecules penetrate cells by diffusion, which is less cancer-selective in vitro. The researchers hypothesize that the molecules they have developed are less toxic to healthy cells because they are internalized less.
In the next stage of developing M-TKs, research efforts will focus on the mechanism of action of the M-TKs; but to determine whether their ROS-mediated toxicity involves specific intracellular targets. Hence, these findings confirm the viability of studying the effects of these compounds in whole vertebrates; as the M-TKs were well tolerated by zebrafish and appeared to selectively attack dividing cells.
Other NYUAD collaborators include fourth year graduate PhD student Tina Skorjanc; who contributed to the paper’s biological-related aspects. But the research was carried out using the Core Technology Platform resources at NYUAD, which are shared facilities that support research activities across disciplines.