Investigating the use of iron chelator deferoxamine (DFO)-bearing PEG-like nanoprobes as a multifunctional agent for cancer therapy and PET imaging
Mentor: Georges El Fakhri, PhD (Harvard Medical School)
Iron is an essential element in the growth and division of cells, including cancer cells. Chelation, the bonding of metal ions via weak electrostatic interactions between the metal ion and atoms of a molecule, can be used to remove metals from the body, in order to protect from metal-induced toxicity. This strategy may also be attractive for the induction of cytostasis in metabolically active cells, depriving them from iron that is used in various key intracellular processes, including electron transport in the mitochondria. The iron chelator deferoxamine (DFO) has been approved for treatment of iron overload, and due to its potential and lack of toxicity, is now being examined for other therapeutic, and imaging uses. The El Fakhri lab has developed PEG-like nanoprobe (PNs) with three functional groups that can be engineered independently to alter fluorescence, pharmacokinetics and metal chelating activity. PNs bearing DFO can be imaged using PET imaging, when bound to 89Zr, which is a radioactive metal ion that can be effectively and stably chelated by DFO. Uptake and internalization of 89Zr-DFO-PNs in tumor and cultured cells can be observed with PET, in vivo fluorescence emission, fluorescence microscopy and flow cytometry. Accumulation of these DFO-bearing PNs labeled with fluorochrome were used for the in vivo imaging of different disease models, including tumors, transient ischemic brain lesions and sites of inflammation. Initial results indicated that DFO-PNs can inhibit cell growth in at least one tumor cell line, and this project aims to identify the molecular mechanisms of PN iron-sequestration-based toxicity and demonstrate this application in different unique cancer and normal cell lines, in hopes of supporting the use of DFO-PNs in clinical applications as antitumor and anti-inflammatory agents that can be used for diagnosis and therapy.
Schematic summarizing approach of iron chelation therapy in cancer. Cancer cells utilize free iron to carry out critical intracellular processes. PEG-like nanoprobes bearing DFO serve as chelating agents to remove iron from targeted cancer cells, halting intracellular processes, further resulting in cytostasis. Source: