Invention:
Novel molecular design extends the reach of iron chelators to applications in cancer chemotherapy. This invention not only recognizes the higher demand of iron that characterizes cancer cells, but also takes into account other physiological differences between malignant cells and the surrounding tissue. Specifically, pro-drugs are designed to activate into iron chelating agents within the reducing environment of the cytoplasm of cancer cells. The pro-chelators may be used to target malignant cells or in the treatment in a condition associated with metal ion dysregulation. The pro-chelators may be conjugated to a carbohydrate moiety, which may increase their selectivity for cells that overexpress glucose transporters, for example malignant cells.
Background
Basic and clinical research has improved significantly the prognosis and number of treatment options for cancer patients in the past decades. Broad-spectrum cytotoxins and their unwanted side effects, however, continue to be part of cancer chemotherapy in the clinical practice. Current research efforts are responding to the pressing need for more targeted, less toxic treatment options. Such approaches are necessarily based on new or previously overlooked information on the genetic and/or metabolic makeup of cancer cells, particularly on peculiarities that differentiate them from normal cells within the same tissue. We pursue the molecular design of strategies to study and exploit an aspect of cancer metabolism that is not targeted by current clinical chemotherapy, namely the altered iron metabolism of malignant cells.
In order to sustain their rapid proliferation rates, cancer cells require higher iron content when compared to normal cells. As such, the use of small-molecule scavengers (chelators) of iron ions could deprive cancer cells of this essential supply, thereby slowing or halting cancer growth. Indeed, chelation therapy has been employed clinically for decades in cases of iron overload conditions associated with genetic disorders, such as thalassemia and hemochromatosis. The key to the success of chelation therapy in cancer treatment, however, is the ability to target iron ions in malignant cells without affecting iron levels in the bloodstream and in normal tissue. Lacking such selectivity, currently available chelators were found to elicit adverse side effects when employed in the context of cancer research.
Applications
- Intracellular iron chelation, targeted at cancer therapy
- Treatment of metal ion dysregulation, including iron overload
Advantages
- Reduce proliferation of malignant cells
- Improve selectivity for iron chelation within malignant cells
- Targeted treatment for iron overload
