Metal-organic compounds, or hybrid structures containing metals as well as molecules that incorporate carbon and other atoms, have been a mainstay in cancer therapy. Advancements show that synthesizing three-dimensional (3D) knot complexes of these structures enhances their ability to fight selective cancer cells. Ali Trabolsi and colleagues from New York University Abu Dhabi and the University of Rochester published the results of a series of experiments on these in a recent issue of Chemical Science.

“The use of metal-organic non-trivial structures such as links and knots as anticancer agents is unprecedented, and to our knowledge, [this study is] the first of its kind,” says Trabolsi, associate professor of chemistry at New York University Abu Dhabi. The results of these studies, he says, “will be fundamental to the progression of clinical studies on these complexes, which may determine new candidates for modern chemotherapy in the next few years.”

The use of inorganic compounds in cancer therapy, specifically those containing metals, is no novel concept. For example, organo-platinum complexes, such as those used in the cancer drugs cisplatin, carboplatin, and oxaliplatin, have been frequently used in many cancer patients who require some form of chemotherapy.

Metals have several special properties that make them suitable agents that researchers can use when designing drugs that target specific cells or protein. More specifically, metal-organic compounds possess some versatile stereochemical properties that enable scientists to synthesize a diverse array of metal-organic complexes that have shapes that complement those of biological targets. The redox activity of metals such as iron and cadmium also promotes cellular destruction, aiding in curtailing the proliferation of cancer cells. Another attractive property of metal-organic complexes is that their metal-ligand bonds exhibit acid-lability (i.e., instability that results in chemical reactions when subjected to acids), which has proven to be useful in targeting cancer cells since the extracellular environment of cancerous tissue is often more acidic than normal tissue. Finally, in comparison to organic molecules, organometallic compounds are fairly simple to synthesize and modify.

Trabolsi’s study expanded on a previous study in which his research team established a protocol for the synthesis of zinc- and cadmium-containing trefoil knots. The researchers demonstrated the metal-trefoil knot’s (M-TK) biological activity and selectivity by conducting a series of in vivo and in vitro experiments in which they introduced the M-TK agents to six lines of cancers known to be highly resistant to drug therapy: human cervical epithelial carcinoma and human prostate adenocarcinoma along with two types of human ovarian carcinoma and two types of human breast adenocarcinoma. The cells subjected to metal-free TK exhibited minimal toxicity, whereas the M-TK-treated cells died. In fact, the M-TKs exhibited stronger cell toxicity than cisplatin, a highly cytotoxic chemotherapy drug used in many cancers.

Reactive oxygen species (ROS) refers to molecules that have become unstable—or reactive—through oxidation. ROS activity is a major driver of natural programmed cell death or apoptosis; it is also a toxicity mechanism associated with many metals. Researchers evaluated M-TK ROS activity by using a fluorescent dye to observe whether cells became stained—a sign that the cells had become damaged by perforation, which allowed the dye to seep in. While cells treated with camptothecin (an anticancer drug, also known as CPT) or cisplatin for three hours had roughly twice (7%) the amount of ROS than that found in healthy control cells (3.6%), M-TK-treated cells had much higher concentrations of ROS, ranging from 11% to 20%.

The research team also conducted a series of experiments to determine the effects of M-TKs on mitochondrial activity, toxicity, and to elucidate the mechanism of apoptosis. They found that while M-TKs clearly encourage ROS-induced mitochondrial damage, the metal-organic compounds leave the nuclear DNA and the plasma membrane undisturbed. This is important because corrupted DNA could result in greater toxicity since cells with altered DNA could have abnormalities or result in abnormal cellular behavior.

“The key outcome of these studies is to find novel metal complexes that could potentially overcome the hurdles of current clinical drugs including toxicity, resistance, and other pharmacological deficiencies,” Trabolsi says. “Our work will be of interest to chemists, medicinal chemists, and biologists.”

Chemistry Nobel laureate and professor at Northwestern University Sir Fraser Stoddart says these findings have cracked the door open for unlimited potential for additional metal-organic research. “Entangled structures have been waiting more than 60 years to find some real applications and that’s what the Trabolsi group is offering to the scientific community,” says Stoddart, who did not participate in the study. “The use of metal-organic non-trivial structures such as links and knots as anticancer agents is unprecedented.”

Read the article in Chemical Science.