Isotopic Labeling of Biotherapeutics

Cancer is well-known in modern society as a difficult disease to cure. However, thanks to scientific research, treatments to effectively heal its multiple variants are rapidly increasing in both efficiency and success rate. Leukemia, a frequent type of cancer, affects the blood and bone marrow, which is the spongy tissue inside bones where blood cells are made. It occurs when the body produces an excessive number of abnormal white blood cells, making it difficult to fight infections.

 

Recently, epigenetics—the study of how genes can be turned on or off without changing the underlying DNA sequence—has shown promise in developing new, efficient ways to treat leukemia by normalizing gene expression, which is often compromised in cancer cells. This involves using modified nucleosides that can suppress the processes involved in cancer’s uncontrolled multiplication and induce programmed cell death (apoptosis) in malignant cells.

 

Decitabine (1) is an epigenetic drug currently used to treat leukemia, but it still has stability problems once injected into a living system. Recently, our group was able to produce a variant of this molecule that seems to avoid some of the issues decitabine has. The objective of my research is to understand the behavior and track the metabolic pathways of this new epigenetic drug, cAzadC(2). This will involve first creating a quantification standard and then developing a radio-labeled version that can effectively trace the drug's fate once it is injected into a living system.

 

To further understand the mechanism of action of our new molecule and decitabine, we produced a slightly modified variant of our epigenetic drug, cdC (3). This modification will allow us to better understand the function of the active site of the molecule.

 

After establishing a method for comparison to deeply investigate the molecule, we developed a high-quality heavy-labeled standard, [15N3]-cAzadC (4). This will enable us to precisely quantify the amount of our molecule incorporated into the living system.

 

In conclusion, we developed a new molecule to compare with our promising epigenetic drug, as well as a heavy-labeled standard to accurately quantify it. Our next goal is to synthesize a radio- labeled version of cAzadC (5) to track the fate of our molecule inside a living system, including its absorption, distribution, metabolism, and excretion.